Table of contents :

Viruses

• dsDNA viruses, no RNA stage
• Adenoviridae : the adenoviruses: a family of DNA viruses having a nonenveloped icosahedral virion 80–110 nm in diameter with 252 capsomers. The genome consists of a single linear molecule of dsDNA (MW 20–30 x 10⁶, size 36–38 kbp). Viruses contain at least 10 structural proteins and are ether-resistant and acid-stable; some are heat-sensitive. Replication occurs in the nucleus and structural proteins are synthesized in the cytoplasm; assembly occurs in the nucleus and virions are released by cell destruction. Host range is generally narrow and transmission may be direct or indirect. Genera include :
• Aviadenovirus : adenoviruses of birds; a genus of viruses of the family Adenoviridae that infect many bird species, causing a wide variety of diseases; infection by some viral species is asymptomatic. Species names are abbreviated by a prefix derived from the host genus and a number designating the serotype, e.g., DAdV-2 for duck adenovirus 2.
• Mastadenovirus : mammalian adenoviruses; a genus of viruses of the family Adenoviridae that infect mammals, causing disease of the respiratory tract, gastrointestinal tract, conjunctiva, central nervous system, and urinary tract; infection may be asymptomatic. Many species induce malignancy. Human viruses are grouped into 7 subgenera (A–G) on the basis of structural, immunological, biological, and chemical characteristics :
• Human mastadenovirus A
• Human adenovirus 12

=> CNS infections in immunocompromised hosts
=> croup
Induces tumor in hamster babies.
• Human adenovirus 18
• Human adenovirus 31
=> febrile respiratory infection and diarrhoea
• Human mastadenovirus B
• Human adenovirus 3 / pharyngoconjunctival fever virus
=> morbilliform maculopapular exanthema
=> pharyngoconjunctival fever (PCF)
=> epidemics of aspecific acute pharyngitis, acute bronchitis or interstitial pneumonia
• Human adenovirus 7
• Human adenovirus 7a
=> pharyngoconjunctival fever (PCF)
=> epidemics of aspecific acute pharyngitis, acute bronchitis or interstitial pneumonia ("recruit fever")
=> morbilliform maculopapular exanthema
=> CNS infections in immunocompromised hosts
Induces tumor in hamster babies.
• Human adenovirus 7d
• Human adenovirus 11
• Human adenovirus type 11 (Ad11A) (strain BC34)
• Human adenovirus type 11 (Ad11P) (strain Slobiski)
=> acute hemorrhagic cystitis in babies
=> acute hemorrhagic conjunctivitis
• Human adenovirus 14
 increasingly recognized in severe acute respiratory illness in both military and civilian individuals
=> pharyngoconjunctival fever
=> epidemics of acute bronchitis or interstitial pneumonia ("recruit fever")
• Human adenovirus 16

Induces tumor in hamster babies.
• Human adenovirus 21
=> epidemics of aspecific acute pharyngitis, acute bronchitis or interstitial pneumonia ("recruit fever")
=> acute hemorrhagic cystitis in babies
• Human adenovirus 34
• Human adenovirus 34a
=> interstitial pneumonia with dissemination or urinary tract infections (UTI) in immunocompromised hosts
• Human adenovirus 35
• Human adenovirus 35p
=> interstitial pneumonia with dissemination or urinary tract infections (UTI) in immunocompromised hosts
• Human adenovirus 50
=> often-fatal illnesses in immunocompromised individuals, including bone marrow transplant recipients and cancer and AIDS patients
• Human mastadenovirus C
• Human adenovirus 1
=> morbilliform maculopapular exanthema
=> pharyngoconjunctival fever
• Human adenovirus 2
=> morbilliform maculopapular exanthema
=> pharyngoconjunctival fever (?)
=> febrile respiratory infection and diarrhoea
• Human adenovirus 5
Proteomics : it up-regulates c-PI31, which delays immunoproteasome formation hence affecting presentation of the immunoproteasome-dependent epitope E1B. E1A interacts with the 19S S4 ATPase subunit of the 26S proteasome.
=> interstitial pneumonia with dissemination or urinary tract infections (UTI) in immunocompromised hosts
=> morbilliform maculopapular exanthema
=> pharyngoconjunctival fever
• Human adenovirus 6
=> pharyngoconjunctival fever
=> pertussis-like syndrome : a syndrome clinically indistinguishable from pertussis but in which there is no evidence of infection with Bordetella pertussis or Bordetella parapertussis, although evidence of other infectious agents, such as adenoviruses types 1, 2, 3, 5, and 6, can be demonstrated
• Human mastadenovirus D
• Human adenovirus 8 / epidemic keratoconjunctivitis virus
=> epidemic keratoconjunctivitis (EKC)^ref

• Human adenovirus 9
• Human adenovirus 10
• Human adenovirus 13
• Human adenovirus 15
• Human adenovirus 17
• Human adenovirus 19
=> epidemic keratoconjunctivitis (EKC)
• Human adenovirus 19a
• Human adenovirus 19p
• Human adenovirus 20
• Human adenovirus 22
• Human adenovirus 23
• Human adenovirus 24
• Human adenovirus 25
• Human adenovirus 26
• Human adenovirus 27
• Human adenovirus 28
• Human adenovirus 29
• Human adenovirus 30
• Human adenovirus 32
=> CNS infections in immunocompromised hosts
• Human adenovirus 33
• Human adenovirus 36
=> obesity (RR = 5-6)
• Human adenovirus 37
=> epidemic keratoconjunctivitis (EKC)
• Human adenovirus 38
• Human adenovirus 39
=> interstitial pneumonia with dissemination or urinary tract infections (UTI) in immunocompromised hosts
• Human adenovirus 42
• Human adenovirus 43
• Human adenovirus 44
• Human adenovirus 45
• Human adenovirus 46
• Human adenovirus 47
• Human adenovirus 48
• Human adenovirus 49
• Human adenovirus 51
• Human adenovirus 53
• Human adenovirus 54
• Human adenovirus 58
• Human adenovirus 60a
• Human adenovirus 62
• Human adenovirus 63
• Human adenovirus 64
• Human adenovirus 65
• Human adenovirus 67
• Human adenovirus 69
  
• Human mastadenovirus E
• Human adenovirus 4
• Human adenovirus 4a
=> epidemic aspecific acute pharyngitis, acute bronchitis or interstitial pneumonia ("recruit fever")
• Human mastadenovirus F
• Human adenovirus 40
• Human adenovirus 41
=> acute gastroenteritis after 24-72 hours incubation => cholangiohepatitis occurs in immunocompromised hosts as a result of ascending infection from the gastrointestinal tract to the biliary tree.

• Human mastadenovirus G
• Human adenovirus 52
one of only three gastroenteritis-causing HAdVs that are equipped with two different fiber proteins, one long and one short. terminal knob domain of the long fiber (52LFK) binds to CAR, and the knob domain of the short fiber (52SFK) binds to sialylated glycoproteins^ref

• titi monkey adenovirus (TMAdV) : the scientist who fell ill had been in close contact with Titi monkeys of a colony at the California National Primate Research Center in Davis of 55 monkeys housed at the center, 23 (about 40%) became seriously ill with upper respiratory symptoms that progressed to pneumonia and an inflammation of the liver. A total of 19 monkeys, or about 83% of those infected, died . Though she became seriously ill with pneumonia around the same time the monkeys were falling ill, she was not hospitalized and recovered after about 4 weeks. Her blood tested positive for antibodies to the virus 3 months after the epidemic^{ref1, ref2}
  
Epidemiology : outbreaks of adenovirus infection are not uncommon in military establishments, and some types of adenovirus infection have been associated with conjunctivitis in the past. In Feb 2004 following an outbreak of conjunctivitis affecting about 230 soldiers in 6 barracks in northern and southern Hessen, some 4700 members of the 14000 troops stationed in Hesse by the German Federal Armed Forces have have been withdrawn from service. The bases at Schwalmstadt (where the epidemic began), Schwarzenborn, Stadtallendorf, and Neustadt will be closed for 3 weeks while the premises are disinfected
• Japan : prior to 1995, most isolates were (in descending order) adenovirus types 3, 2 and 1. In 1997, most were types 2, 3 and 7. In 1999, most were types 2, 3 and 1. Adenovirus type 7 infection rates peak during May to September, with 55 percent of patients in the age group 0 to 4 years. An nationwide outbreak of Adenovirus 7 infection (75 cases) was reported in 1995. During 1991 to 2003, laboratory reports ranged from 1200 to 3000 per year.
• 17 032 isolates were recovered during 1982 to 1993 (includes 1080 in 1993): 6722 respiratory, 3428 eye and 1605 gastrointestinal.
• 10 010 isolates were recovered during 1995 to 1999: 7207 respiratory, 1321 eye and 1677 gastrointestinal.
• reports for 2003 included 886 isolates of adenovirus type 3; and 1421 respiratory, 84 eye and 269 gastrointestinal isolates.
Reports of pharyngoconjunctival fever ranged from 6249 (in 1997) to 15 812 (in 1991).
•  these data represent cases reported by general physicians, internists and ophthalmologists.
•  40,714 cases of pharyngoconjunctival fever were reported by pediatric sentinel clinics in 2003.
Notable outbreaks:
• 1973 : an outbreak (28 cases) of adenovirus 8 epidemic keratoconjunctivitis was reported at a babies' home in Sapporo.
• 1990 (publication year) : an outbreak (14 cases) of adenovirus 37 keratoconjunctivitis was reported in an ophthalmology clinic in Yokohama.
• 1996 to 1997 : an outbreak (14 cases) of severe adenovirus 7 infection was reported on a pediatric ward in Hokkaido.
Proteomics :
• serotypes A, C, D, E and F all use :
• primary receptor : Coxsackievirus B and Adenovirus receptor (CAR / CVADR / CXADR), which interacts with the head domain of the adenoviral fiber protein, also called fiber knob. CAR is almost ubiquitously expressed (expecially in hepatocytes). Adjacent epithelium cells maintain cell contacts through homotypic interactions of the CAR protein, an immunoglobulin superfamily member that also serves as the receptor for adenoviruses. However, CAR exhibits polarized basolateral expression and might block virus escape to the apical surfaces when viral progeny are shed on basolateral surfaces. But adenoviruses express the protein fiber, which competitively inhibits CAR-CAR interactions, disrupting epithelial integrity. Thus, fiber is an adenovirus virulence factor that promotes viral dissemination. After the initial binding step, the viral particle achieves endocytotic internalization via interaction with ...
• secondary receptors : a_vb₃ , a_vb₅ (and a_vb₁?) integrins, which interact with the penton base. Integrin a_M mediates attachment but not internalization of adenovirus virions in monocytes, while integrin a_V also mediates internalization via clathrin-dependent endocytosis in both monocytes and epithelial cells.
• serotype B uses CD46 / MCP as receptor
Adenovirus internalized by alveolar macrophages is degraded with a half-life of 6 h while in epithelial cells < 5% is degraded by 48 h.
Genomics : it integrates into adenovirus/SV40 integration site 1 (ASVS1)
• E1B19K is a Bcl-2 ortholog.
They persist in lymphoid tissues, rhinopharynx, bowel and kidney (excreted in urines during pregnancy).
=> clinical manifestations : adenovirus infections are usually asymptomatic, but may be associated with diseases of the respiratory, ocular and gastrointestinal tract (types 40 and 41). It has been estimated that adenoviruses are responsible for 5-10% of paediatric respiratory infections (predominantly pharyngoconjunctival fever (PCF)). Respiratory infections in children are short-lived and rarely life-threatening. Outbreaks of adenovirus respiratory infections have been common among military recruits (mainly types 4, 7, 14 and 21), where rates of hospitalisation have reached 20%. As a result vaccines were developed against adenovirus types 3, 4, 7  and 21, but later withdrawn. Most outbreaks of pharyngoconjunctivital fever in school-age children have occurred occur during the summer, whereas the outbreaks among military recruits have occurred during winter, probably reflecting a different mode of transmission. Adenovirus types 8, 9 and 11 have been associated with outbreaks of keratoconjunctivitis (also known as shipyard eye) in adults. However, whereas multiple serotypes from different species have been described as causing cases or limited, irregular outbreaks of ocular disease in humans, there are only a few serotypes that regularly cause larger outbreaks or epidemics. The 2 types of ocular disease that are commonly caused by adenoviruses are pharyngoconjunctival fever (PCF) and epidemic keratoconjunctivitis (EKC). An interesting observation is that the 3 serotypes that cause EKC (Ad8, Ad19, and Ad37) use a cellular receptor (sialic acid) that is different from the cellular receptors used by other adenoviruses (CAR or CD46)
Laboratory examinations : basophilic Cowdry type B inclusion bodies
Therapy : at present, there are no licensed antivirals available to any of the adenoviruses. Cidofovir intravenously at 5 mg/kg weekly for 2 consecutive weeks, then every 2 weeks until 3 consecutive ADV-negative samples were documented from all previously invoved sites is safe and effective in pediatric HSCT recipients^ref
Prevention : an adenovirus type 4 vaccine and a triple type 4, 7 and 21 vaccine were employed with some degree of success in the USA. However, these vaccines are no longer in production, and there is some evidence that outbreaks of adenovirus-associated illness affecting military recruits are on the increase.
Used as transfection vector.
• Herpesviridae : the herpesviruses: a family of DNA viruses having a virion 102–200 nm in diameter consisting of four components: a lipid bilayer envelope with surface projections, a tegument of amorphous material, an icosahedral nucleocapsid with 162 prismatic capsomers, and a protein spool on which the DNA is wrapped. The genome consists of a single molecule of linear double-stranded DNA (MW 70–150 x 10⁶, size 124–235 kbp). Viruses contain at least 20 structural polypeptides and are sensitive to lipid solvents, heat, and extremes of pH. Replication occurs in the nucleus and the envelope is acquired by budding through the inner lamella of the nuclear membrane; virions are released by transport via the endoplasmic reticulum to the cell membrane. Persistence for the lifetime of the host is common and some herpesviruses induce neoplasia. Except cercopithecine herpes virus 1 and pseudorabies virus, all human herpesviridae are species-restricted.
  

One strategy used by human alpha- and gammaherpesviruses to facilitate such competition is to shut off the expression of host genes located in the nuclear genome. Host shutoff involves inhibition of host gene transcription, alterations in mRNA processing, and the loss of cytoplasmic mRNAs. Altogether, these effects help redirect the cellular gene expression machinery toward the expression of viral genes. Interestingly, herpes simplex virus type 1 (HSV-1), HSV-2, and Epstein-Barr virus (EBV) have also evolved mechanisms to disrupt the expression of genes located in the host mitochondrial genome by degrading mitochondrial DNA (mtDNA)^ref

There are 3 subfamilies :

• Alphaherpesvirinae
• Simplexvirus
• cercopithecine herpes virus 1 / monkey B-virus / herpesvirus simiae / herpes virus B
Epidemiology : secondary transmission after a lab accident^{ref1, ref2}. In Jan 2005 4 Formosan rock monkeys (Macaca cyclopis) out of 27 in a wildlife shelter in Nantou County were put down after they were diagnosed as carriers
Genomics : there is evidence of distinct genotypes, and that isolates from different species of macaques vary in their pathogenicity for humans.
Transmission : the natural host is Asiatic macaque monkey, but, when reactivated, can be transmitted to humans usually via injury (bites and scratches), through handling infected monkey tissues, and more rarely by other routes such as the eye. B virus infection of humans is mainly restricted to animal handlers and pet owners, but there is a low risk in any contact with macaques
=> the incubation period in humans can be as short as 2 days, but several weeks is more common. Minor symptoms are followed quickly by severe ascending myelopathy, acute meningoencephalitis, and death
=> in 1997 mucocutaneous infection without injury was reported.
Prevention : if bitten or scratched, people should thoroughly cleanse their wounds with water and receive an immunoglobulin shot.
Prognosis : the death rate can be as high as 79%, and recovered patients may have neurologic impairment. However, the use of the antivirals acyclovir or gancyclovir can halt disease progression and assist recovery. Rapid diagnosis is essential
• human herpesvirus 1 (HHV-1) / herpes simplex virus 1 (HSV-1) / herpesvirus hominis 1 (HVH1)
Proteomics :
• glycoprotein B (gB) : HSV-8p is an immunodominant peptide
• glycoprotein D (gD) binds to herpesvirus entry mediator (HVEM) / herpesvirus entry protein A (HveA) / TR2 / LIGHTR : the BTLA binding site on HVEM overlaps with the binding site for the gD, but is distinct from where LIGHT binds, yet glycoprotein D inhibits the binding of both ligands, potentially nullifying the pathway^ref. Coreceptors : herpesvirus entry protein B (HveB) / poliovirus receptor-related 2 (PVRL2) / CD112 / CD155 and herpesvirus entry protein C (HveC) / poliovirus receptor-related 1 (PVRL1) / nectin-1 / herpesvirus Ig-like receptor (HIgR) (that confined with E-cadherin to adherens junctions in epithelial cells is not very accessible to virus, whereas dissociation of cell junctions releases nectin-1 to serve more efficiently as an entry receptor)
• herpesvirus entry protein B (HveB) / poliovirus receptor-related 2 (PVRL2) / CD112 (expressed in some human neuronal cell lines, fibroblastic cells, keratinocytes, and primary activated T lymphocytes) mediates the entry of 3 mutant HSV-1 strains (HSV-1(KOS)Rid1 ) that cannot use HVEM as co-receptor, but not wild-type HSV-1 strains
• ICP47 inhibits TAP.
• g34.5 dephosphorylates eIF2a and inhibits the shutoff of protein synthesis in metabolically-stressed host cells
• latency-associated transcript (LAT) is the only viral gene expressed during latent infection in neurons. LAT inhibits apoptosis and maintains latency by promoting the survival of infected neurons. No protein product has been attributed to the LAT gene and the mechanism by which LAT protects cells from apoptosis is not yet known. A miRNA encoded by the HSV-1 LAT gene confers resistance to apoptosis. Neuroblastoma cells transfected with a fragment of the LAT gene show reduced susceptibility to cell death. The anti-apoptotic function of LAT has been mapped to a region within the first exon. miR-LAT is generated from the exon 1 region of the HSV-1 LAT gene. The LAT miRNA accumulates in cells transiently transfected with the LAT gene fragment or infected with a wild-type strain of HSV-1. A mutant virus in which a 372-nucleotide fragment encompassing the mature miRNA was deleted neither protected the infected cells from apoptosis nor generated an miRNA. miR-LAT exerts its anti-apoptotic effect by downregulation of TGF-b₁ and SMAD3 expression, both of which are functionally linked in the TGF- pathway. The miRNA encoded by the HSV-1 LAT gene regulates the induction of apoptosis in infected cells by modulation of TGF- signalling and thus contributes to the persistence of HSV in a latent form in sensory neurons^ref
Transmission : oro-oral route
Pathogenesis : antibody-dependent enhancement (ADE) of viral infection. HSV-1 reduces CD1d surface expression on APCs. HSV-1 did not inhibit CD1d protein synthesis or enhance constitutive CD1d endocytosis. Instead, HSV-1 prevented the reappearance of endocytosed CD1d on the cell surface by redistributing endocytosed CD1d to the lysosome limiting membrane. HSV-1 might also inhibit the transport of newly synthesized CD1d to the cell surface. Such inhibition of CD1d surface expression impaired APC–mediated stimulation of NKT cells, supporting the idea that this mechanism may be an important HSV-1 immune evasion strategy^ref.
=> 95% of herpes up the waist and 40% of herpes down the waist
• at 1^st infection (early childhood) : after 2-12 days incubation
• herpetic gingival stomatitis (HGS) and oropharyngitis in babies before age 3 (the most common kind of primary infection) => eschar (=> squamous lip carcinoma), self-limiting within 10-14 days.
• herpetic fever : primary infection with HSV, with diffuse involvement of mucous membranes of the mouth and lips and the surrounding skin; fever and sometimes chills occur.
• recurrent herpes simplex labialis (HSL) / fever blisters / cold sores (prevalence : 20-40% of the US population) : in a normal person, the blister is gone 3-4 days after it appears. In an immunocompromised host, reactivation usually causes chronic ulcers that erode and spread. The lower lip is more commonly affected than the upper lip.
• multiple peri-orificial herpetic lesion in an immunocompetent patient^ref
  
• eczema herpeticum (a kind of Kaposi's varicelliform eruption (KVE)) in individuals who have active or quiescent atopic dermatitis (AD).
• herpes gladiatorum / rugby player herpes / scrum-pox : HHV-1 infections are not uncommon among wrestlers, rugby players and others engaged in contact sports, with no single strain responsible for outbreaks^ref. In the case of wrestlers the condition is known as herpes gladiatorum (HG). Anderson^ref concluded from an analysis of the epidemiology and clinical analysis of several outbreaks of herpes gladiatorum that the National Federation of State High School Associations (NFHS) guidelines were inadequate to prevent and control outbreaks of HG. The focus of preventive efforts needed to change from mat cleanliness to more rapid detection of outbreaks by requiring culture results and appropriate therapy for all suspected bacterial and herpes lesions before allowing return to contact. To minimize and control spread of HG, treatment and isolation should be implemented based not only on vesicle formation but also on systemic signs and symptoms. Anderson (Jpn J Infect Dis. 2006 Feb;59(1):6-9, Feb 2006) has described subsequently the prophylactic use of valacyclovir (an inhibitory nucleoside analogue prodrug) to prevent outbreaks of primary herpes gladiatorum at a 28-day wrestling camp. The study evaluated the usage of valacyclovir to prevent acquisition of primary HG, due to human herpesvirus type 1, in high school wrestlers at a 28-day wrestling camp. At the beginning and end of camp, IgM and IgG anti-HSV-1 antibodies were collected. Out of 332 male wrestlers, aged 13-20, who entered camp, 94 elected to participate in blood sampling. 64 were on antiviral medication. Among the 94 wrestlers, 28 (29.8%) had positive IgG anti-HHV-1 titers. Of this group, 66 of 94, were human HHV-1 IgG seronegative. At the end of camp, 55 of these original seronegative individuals elected to participate in blood sampling and none had detectable IgM anti-human herpesvirus 1 or 2 antibodies. Compared to previous years without antiviral usage, introducing prophylactic valacyclovir reduced clinical HG outbreaks by 87% at this 28-day wrestling camp. Due to the high prevalence of this virus in high school wrestlers, Anderson recommended that serological testing should be done at the beginning of each season. HSV-1 seropositive individuals should consider being on antiviral medication throughout the season to minimize the risk of transmitting the virus to other wrestlers.
• herpetic whitlow (pustules on the finger or hand due to bacterial superinfection, often seen in health cares workers (dentists, ..) who have a tendency to touch HSV lesions without dressing gloves)
• proctitis
• non-gonococcal urethritis (NGUs)
• temporal lobe encephalitis in adults => epilepsy
• Alzheimer's disease (?)
• ocular herpes : herpetic stromal keratitis (HSK) (type II hypersensitivity mediated by T_h1 effector cells) leading to scarring, opacity, and blindness, and it is an important problem in common corneal surgeries or acute monolateral follicular conjunctivitis. In the preclinical phase, when HSV-1 replicates in the corneal epithelium, neutrophils invade the underlying corneal stroma. This transient response, triggered by replicating virus, is thought to control HSV replication and limit viral spread into peripheral tissues. During the clinical phase, a second wave of inflammatory cells, predominantly consisting of neutrophils, infiltrates the corneal stroma and destroy it. Paradoxically, virus antigens are largely focused in the epithelial layer of the cornea and not in the stromal layer, and viral antigens are eliminated before stromal inflammation develops. It is not clear what drives inflammation, whether viral antigens are necessary, or how viral antigens reach the stroma. It has been proposed that HSV travels from the corneal epithelium to sensory ganglia then returns to the stroma to cause disease. However, there is also evidence of HSV DNA and infectious virus persistent in corneas, and HSV can be transmitted to transplant recipients. US9^- HSV mutant, that had diminished capacity to move in neuronal axons, replicated and spread normally in the mouse corneal epithelium and to the trigeminal ganglia. However, US9^- HSV was unable to return from ganglia to the cornea and failed to cause periocular skin disease, which requires zosteriform spread from neurons. Nevertheless, US9- HSV caused keratitis. Therefore, herpes keratitis can occur without anterograde transport from ganglia to the cornea, probably mediated by virus persistent in the cornea^ref.
• disseminated infection in immunocompromised individuals (herpes esophagitis, interstitial pneumonia : lethality 50%)
• at reactivations : papules => vesicles
• Behçet-Adamantes-Gilberto syndrome (?)
• type IA insulin-dependent diabetes mellitus (?)
Laboratory examinations : Cowdry type A inclusion bodies (Lipschutz inclusions), owl-eye inclusions
Experimental animal models : Callithrix jacchus is more susceptible to HSV-1 encephalitis than Aotus trivirgatus (expensive, difficult to obtain and to maintain in captivity)
Used as transfection vector.
Therapy : acyclovir; alcoholic povidone-iodine^ref
• human herpesvirus 2 (HHV-2) / herpes simplex virus (HSV-2)
Proteomics : glycoprotein D (gD) binds to herpesvirus entry mediator (HVEM) / TR2 / LIGHTR. Coreceptors : herpesvirus entry protein B (HveB) / poliovirus receptor-related 2 (PVRL2) / CD112 / CD155 and herpesvirus entry protein C (HveC) / poliovirus receptor-related 1 (PVRL1) / nectin-1 / herpesvirus Ig-like receptor (HIgR)
=> 5% of herpes up the waist and 60% of herpes down the waist (genital herpes) (sexual route). About 25-30% of people age 18-29 years are seropositive for HSV-2 (2/3 of those do not know they have it because many primary infections are often asymptomatic.  The worst primary disease occurs in people who are seronegative for HSV-1.
• at 1^st infection (early childhood) : after 2-12 days incubation
• genital herpes / herpes genitalis or progenitalis (painful lesions) : cervicitis, vulvovaginitis, balanoposthitis, non-gonococcal urethritis (NGUs), proctitis (severe in male homosexuals). The lesions are very superficial (unlike chancroid or syphilis, whose lesions are lumpy). The primary lesions stay for 2-3 weeks, but recurrent usually heal within 3-5 days.
• neonatal herpes (perinatal contagion) => dissemination, encephalitis, and visceral disease (interstitial pneumonia, hepatic necrosis). If the mother has been seropositive for some time before the birth, then transplacental IgG serve as a protective mechanism for the newborn. >50% mortality.
• eczema herpeticum / Kaposi's varicella-like eruption in babies with atopic dermatitis, seborrhoic dermatitis,pemphigus or Wiskott-Aldrich syndrome => generalized herpes (including erythema multiforme, herpetic stromal keratitis (HSK), retinal necrosis)
• Bell’s palsy
• encephalitis when the virus travels up the nerve to the brain instead of down towards the lip (lethality 50%)
• lymphocytic meningitis follows primary genital herpes in 10% of patients. Meningitis may be recurrent in about 30% of patients (recurrent lymphocytic meningitis (RLM) / Mollaret’s meningitis) :. HLA-DRB1*01 and -B*27 alleles and low plasma IgG1 levels may be significant risk factors for RLM^ref
• gingivostomatitis and acute pharyngitis in adults following oro-genital contacts => eschar (=> squamous lip carcinoma)
• cervical squamous cell carcinoma (priming effect for HPV-6, HPV-10, HPV-11, HPV-16, and HPV-18 ?)
It undergoes latency in lumbar and sacral ganglia thanks to latency-associated transcripts (LAT).
• at reactivations it is milder
Laboratory examinations : owl-eye inclusions,Cowdry type A inclusion bodies (Lipschutz inclusions).
Used as transfection vector.
Therapy : acyclovir
Diagnosis : multinucleated giant cells are seen (Tzanck cells)
Chemotherapy : PO  or topic acyclovir or cidofovir (if resistance occurs => foscarnet), idoxuridine, vidarabine and trifluridine.
• Varicellovirus
Proteomics : UL49.5 protein, an interaction partner for glycoprotein M, inactivates TAP via inhibition of peptide transport through a conformational arrest of the transporter and degradation of TAP by proteasomes. UL49.5 is degraded along with TAP via a reaction that requires the cytoplasmic tail of UL49.5^ref
• Human herpesvirus 3 / varicella-zoster virus (HHV-3 / VZV)
Epidemiology :
• USA : chickenpox-related deaths happened in about 100 people a year before 1995, prior to introduction of an improved vaccine. The CDC states that about 40 percent of deaths due to chickenpox happen in children younger than age 10. Research results indicate the current vaccine is about 85% effective in preventing an outbreak. Comprehensive accounts of chickenpox^ref and chickenpox vaccination^ref are available at the CDC website. Varicella is the most common fatal

'childhood disease' in the USA^ref. Varicella ranks 4th among all vaccine-preventable deaths^ref
=> at 1^st infection (90% before age 9) from ...
• inhalatory or conjunctival route : primary viremia and secondary viremia in RES cells => after 10-23 days incubation =>
• varicella / chickenpox:maculopapular exanthema => vesicles (Sklowsky's symptom : when light pressure with the index finger is made upon the healthy skin near, and then over, a vesicle in varicella, the wall of the vesicle easily collapses and the contents are discharged) => pustules with "starry sky" look (contemporaneous presence of papulae, vesicles and scubs on whole body). + salicylates (+ Influenzavirus A H₃N₂ ?) => Reye's syndrome . Sequelae : vesicles, impetigo, neuraxitis, acute glomerulonephritis, acute hepatitis, keratitis, interstitial pneumonia (1%, expecially in immunocompromised adults => death due to respiratory failure), postvaricella purpura fulminans (due to autoimmune thrombocytopenia and DIC),  lupus anticoagulant (LAC), cerebellitis (=> ataxia), post-infective encephalitis (PIE : 1 case out of 4,000-10,000), overinfection by Streptococcus pyogenes (expecially necrotizing fasciitis and TSLS) => thrombosis. Lifelong presence of neutralizing antibodies prevents reinfection. Virus undergoes latency in satellite cells of a sensitive ganglion.
• modified varicella-like syndrome (MVLS) in vaccinated individuals : shorter and milder
• transplacental route :
• if mother becomes affected before pregnancy month 4 => eye, brain and limbs injuries in newborn
• if mother becomes affected just 5 days before the birth => 30% lethality in newborn
=> endogenous reactivation during cell mediated immunity depression => (herpes) zoster / zona / shingles on the unilateral dermatomere innerved by the sensitive nerve in whose dorsal ganglion VZV had undergone latency :Herpes zoster is unusual in persons younger than 10 years of age, and when it does occur in this age group, the lesions have a predilection for dermatomes supplied by the cervical and sacral nerves^ref. In adults, the lesions are more common in the lower thoracic and upper lumbar dermatomes and may involve the trigeminal nerve
• thoracic zoster / Saint Antony fire (T3-T12 dermatomere) > lumbar zoster (L1-L2 dermatomere) > cervical zoster > herpes zoster ophthalmicus (HZO) (if reactivation occurs in ophthalmic or nasociliary branch of trigeminal nerve innervating V1 dermatomere : keratoconjunctivitis and iridocyclitis)
Ramsay-Hunt syndrome if reactivation occurs in geniculate ganglion of facial nerve
herpes zoster oticus if reactivation occurs in uditive nerve
visceral herpes zoster if reactivation occurs in a orthosympathetic or parasympathetic ganglion. Particularly in allogeneic HSCT recipients, visceral disease may precede or occur in the absence of the characteristic signs on the skin^{ref1, ref2, ref3, ref4}. In such cases, in which patients present with severe unexplained abdominal pain, diagnosis and treatment are usually delayed until signs of the infection appear on the skin or, in the absence of a rash, the diagnosis is made at necropsy. In allogeneic BMT recipients, the symptoms may be misdiagnosed as graft-versus-host disease, and immunosuppressive treatment instituted, with potentially grave consequences^ref. In view of the significant morbidity and mortality, early diagnosis of visceral involvement of herpes zoster is highly desirable. A case series of 4 patients with visceral herpes zoster was reported in whom large concentrations of DNA from VZV were detectable in blood by PCR^ref before signs of infection appeared on the skin, thus enabling early diagnosis and treatment^ref
encephalomyelitis
disseminated zoster occurs only in immunodepressions => herpes zoster duplex asymmetricus, interstitial pneumonia, encephalitis
=> post herpetic neuralgia (PHN) : pain that lasts for months to years. More common the older with increasing age and with zoster of the face
=> multiple sclerosis : VZV DNA was detected more frequently (P < 0.05) in the CSF of MS group (31.6%), particularly among the relapsing-remitting MS patients (43.5%), compared with patients with other neurological diseases (10.7%)^ref
An outbreak of cadaver-acquired chickenpox in a health care setting during necropsy^ref
Patients with disseminated, recurrent, or gangrenous zoster, with postherpetic neuralgia, and with ophthalmic zoster are not at elevated risk for subsequent cancer^ref
Laboratory examinations :
• scraping => Tzanck cells, Cowdry type A inclusion bodies, balloon-like CPE
• PCR
• serology :
• anti-VZV IgM at ELISA
• specific IgG avidity index (AI)^ref
Prophylaxis : attenuated vaccine protects from primary infection but not from reactivations; the only way to prevent shingles is eradication via massive antiviral drugs (vidarabine, acyclovir) while having chickenpox, before the virus shelters into ganglia (where drugs can't reach it).
Therapy :
• acyclovir (prodrug : valacyclovir) or famciclovir
• alcoholic^ref or aqueous^refpovidone-iodine
• homologous immune antiserum
• a single epidural injection of steroids and local anaesthetics can lessen pain associated with shingles for 1 month, but the treatment is not effective for the prevention of long-term pain^ref
pseudorabies virus (PrV) / Aujeszky's disease virus (ADV) / suid herpesvirus 1

Receptor : glycoprotein D (gD) binds to herpesvirus entry protein B (HveB) / poliovirus receptor-related 2 (PVRL2) / CD112 / CD155 and herpesvirus entry protein C (HveC) / poliovirus receptor-related 1 (PVRL1) / nectin-1 / herpesvirus Ig-like receptor (HIgR)
Transmission : pseudorabies is most often spread by direct contact between animals but may also be spread by aerosolization. People may carry the virus on their boots, clothing, on trucks or feed equipment between infected sites and non-infected sites ; the virus can remain hidden in nerves of Sus scrofa in a carrier state for long periods of time and then be reactivated. Once introduced into a herd the virus usually remains there and it can continually affect reproductive performance at varying levels. The virus can survive for up to 3 weeks outside the pig. The virus crosses the uterus and placenta and infects the foetuses.
=> Aujeszky's disease :
• pig is the main host :
• sows : cough, fever, nervous signs, reproductive failure, abortions, mummified piglets, stillbirths, birth weak litters. Swine generally appear asymptomatic, and the 1st noticed signs may be abortion, or a high mortality in piglets. Mortality in pigs under a month old may be close to 100%, but only about 10% in pigs as old as 6 months. Other clinical signs include fever, depression, coughing, sneezing, constipation, seizures, ataxia, and circling. Excess salivation may be noticed in both piglets and mature pigs.
• piglets : nervous signs, incoordination, sneezing, coughing, high mortality, low / poor viable piglets
The presence of other infections such as porcine reproductive and respiratory syndrome (PRRS) virus and Leptospira spp. may increase the severity of disease.
• Canis familiaris, Felis catus, ... : nervous signs, death. Infected cattle and sheep show signs of pseudorabies by scratching and biting themselves. Pseudorabies in dogs and cats may manifest itself as sudden death. In cattle, signs include intense itching followed by neurological signs and death. In dogs, signs are evidenced by intense itching,

paralysis of the jaw and pharynx, howling, and death. In cats sudden death without clinical signs often occurs.
• weaners & growers : fever, sneezing, coughing, interstitial pneumonia. Nervous signs including incoordination, fits, Aujeszky's itch / mad itch, and meningitis. Some strains of the virus can cause severe respiratory disease and others severe acute rhinitis. Usually low mortality. However, the pathogenicity to human is controversial : maybe it is dangerous only for immunocompromised hosts.
• Betaherpesvirinae
• Cytomegalovirus
• human herpesvirus 5 (HHV-5) / human cytomegalovirus (CMV) (HCMV) / cytomegalic inclusion disease virus / salivary gland virus
Proteomics : HCMV initially binds to cell-surface heparan sulphate proteoglycans (HSPGs)^ref
• envelope glycoprotein B (gB) / UL55 (4-5 genotypes) binds the receptors
• EGFR : B preferentially binds EGFR and EGFR-ErbB3 oligomeric molecules^ref. HCMV infection results in a rapid decrease in EGFR expression, which implies that the interaction between HCMV and EGFR occurs at an early stage of virus and host contact^ref
• CD209 / dendritic-cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) / CIRE on monocytes (and DCs) and neutrophils (leukotropism)
• annexin II^ref
=> endothelial cells (infected via apical membranes => disrupted cell junction proteins => altered paracellular permeability and cell polarity; if uterine microvascular endothelial cell (UtMVEC) are infected => endovascular cytotrophoblasts => retrograde placental infection), where then it undergoes latency. PMNLs contribute the greatest to the overall viral load in blood (median viral load: PMNLs, 10(5.37) genomes/mL of blood; monocytes, 10(4.40) genomes/mL; B cells, 10(3.70) genomes/mL; and T cells, 10(4.08) genomes/mL). However, monocytes have a viral burden of 0.65 genomes/monocyte which is greater than that within the other leukocyte populations.
• glycoprotein H (gH) binds the coreceptor integrins a₂b₁, a₆b₁, and a_vb₃, which then translocates to lipid rafts where it interacts with EGFR to induce coordinated signaling. The coordination between EGFR and a_vb₃ is essential for the early events of HCMV infection, including viral entry, RhoA downregulation, stress-fiber disassembly and viral nuclear trafficking^ref
• early antigen / pp65 matrix protein binds to NKp30 and inhibits NK cell cytotoxicity^ref
• IE-84 inhibits p53
• m04, m06 and m152 genes are important in evading the host immune system by interfering with the MHC class I pathway
• UL16 glycoprotein binds activating receptor NKG2D ligands UL16 binding proteins (ULBPs) and MICB, retaining them in the cell and effectively masking NK-cell recognition. gp40, the ortholog murine cytomegalovirus (MCMV) protein, disrupts the RAE-1-NKG2D interaction in mice by sequestering RAE-1 molecules, but not H60.
• UL18 is a putative NK lymphocyte decoy
• UL37 / viral mitochondrion-localized inhibitor of apoptosis (vMIA) is a Bcl-2 ortholog. that induces retention of MHC class II⁺ vesicles in an abnormal perinuclear distribution in DCs.
• UL21.5 protein is a small, secreted decoy for CCR whose mRNA is packaged into virions and functions as a high affinity decoy for CCL-5 / RANTES, modulating the host antiviral response even before the newly infecting viral genome becomes transcriptionally active^ref.
• UL144, an orphan TNFR, conserves the binding site on HVEM for BTLA : UL144 binds BTLA, but not LIGHT, and inhibits T cell proliferation, selectively mimicking the inhibitory cosignaling function of HVEM^ref
• US2 catalyse the dislocation of class I MHC products, resulting in the rapid degradation of HLA-DRa and HLA-DMa in DCs.
• US3 retains class I MHC complexes in the ER.
• US6 inhibits TAP
• US11 uses its transmembrane domain to recruit class I MHC products to Derlin-1, a human homologue of yeast Der1p, a protein essential for the degradation of a subset of misfolded ER proteins catalysed by US11, but not by US2^ref. Derlin-1 interacts with US11, a virally encoded ER protein that specifically targets MHC class I heavy chains for export from the ER, as well as with VIMP, a novel membrane protein that recruits the cytosolic p97 ATPase and its cofactor^ref. US11 transports MHC class I H chains back into the cytosol, where they are deglycosylated by host N-glycanase and then degraded by the 26S proteasome
Epidemiology : seroprevalence :
age	heterosexuals	homosexuals	blood donors
18÷29	47.4 %	93.3 %	35.7 %
> 30	62.5 %	93.8 %	45.3 %
every age	54.3 %	93.5 %	42.7 %
Transmission => cytomegalic inclusion disease : any of a group of diseases caused by CMV infection, marked by characteristic inclusion bodies in enlarged infected cells.
• prenatal in utero infection by transplacental route => cytomegalic inclusions disease and IgA deficiency (?).
• post-natal or perinatal infectionin passage through the birth canal or from ingestion of virus in the mother's milk or transfusion : often asymptomatic, but in some there may be hepatosplenomegaly, jaundice, chorioretinitis, purpura, microcephaly, cerebral calcifications, and severe central nervous system sequelae with blindness, deafness, quadriplegia, and mental retardation. Viral excretion in the urine continues for years. The prevalence of maternal CMV infection is 1.2% and among these pregnant women, the incidence of primary and recurrent maternal CMV infection was 0.3% (3 women) and 0.8% (12 women), respectively. Congenital CMV infection was detected in one of the newborns born to mothers with primary infection while no infection was detected in any of the newborns of mothers with recurrent CMV infection, so the incidence of congenital CMV infection was found as 0.1% and the rate of intrauterine infection following the primary maternal infection was 33%^ref. Despite a very high CMV seropositivity rate in mothers of ELBW infants, and the previously reported high rate of CMV excretion into breast milk, the incidence of postnatal CMV transmission is about 2%^ref
• children and adults => acquired disease is transmitted via respiratory droplets, tissue or blood donation, or sexual transmission
• the majority of infections are asymptomatic
• Gianotti-Crosti syndrome (GCS) / papular acrodermatitis of childhood (PAC)
• cytomegalovirus mononucleosis with no pharyngotonsillitis and Downey type I atypical lymphocytes => immunodeficiency, cold agglutinin disease. Samples for direct diagnosis vary with time : oropharyngeal swab => blood => urine. Virus undergoes latency in PBMCs.
• autoimmune diseases :
• type IA diabetes mellitus
• rheumatoid arthritis
• systemic progressive sclerosis
• cardiovascular diseases (24% higher likelihood than unaffected ones)
• reactivation and reinfection in immunocompromised hosts are detected with pp65 antigenemia =>
• postperfusion or post-transfusion mononucleosis or syndrome : cytomegalovirus mononucleosis occurring about 3 to 6 weeks after extracorporeal circulation or multiple blood transfusions in open heart or other surgical procedures
• cytomegalovirus interstitial pneumonia
• myelopathies
• cytomegalovirus meningoencephalitis (Guillain-Barré syndrome)
• glandular involvement, gastro-intestinal ulceration with acute hepatitis
• endocrinopathies
• iridocyclitis and cytomegalovirus chorioretinitis ("pizza pie" look) fist monolateral, then bilateral
• decreased MHC class I expression may enhance NK cell-mediated solid organ allograft rejection :
• kidney transplantation
• acute tubulointerstitial rejection : CMV seromismatched patients (donor⁺/recipient^- or D⁺/R^-) have a 60-80% probability of primary CMV disease and a significantly higher rate of acute rejection than non-seromismatched patients (72% vs. 54.2%, P=0.005). Using multiple logistic regression, CMV seromismatch, delayed graft function, and biological induction were identified as independent predictors of acute rejection. The adjusted odds ratios for these are 2.28, 1.65, and 0.52, respectively. In such cases chemoprophylaxis is justified, at least in those patients who are are found to have 1 or more pp65⁺ cells per 150,000 peripheral WBCs examined (preemptive therapy)
• chronic allograft nephropathy (CAN) : the greater the viral load, the higher the risk of vascular lesion
Long-lasting expansion of Vd2^- gd T cells is a hallmark of HCMV infection in kidney transplant recipients. The ligands of these cells and their role remain elusive. To better understand their immune function, gd T cell clones were generated from several transplanted patients. Numerous patient Vd1⁺, Vd3⁺, and Vd5⁺ gd T cell clones expressing diverse V chains, but not control Vg9Vd2⁺ T clones, displayed strong reactivity against CMV-infected cells, as shown by their production of TNF-a. Vd2^- gd T lymphocytes could also kill CMV-infected targets and limit CMV propagation in vitro. Their anti-CMV reactivity was specific for this virus among herpesviridae and required TcR engagement, but did not involve MHC class I molecules or NKG2D. Vd2^- gd T lymphocytes expressed receptors essential for intestinal homing and were strongly activated by intestinal tumor, but not normal, epithelial cell lines. High frequencies of CMV- and tumor-specific Vd2^- gd T lymphocytes were found among patients' T cells. In conclusion, Vd2^- gd T cells may play a role in protecting against CMV and tumors, probably through mucosal surveillance of cellular stress, and represent a population that is largely functionally distinct from Vg9Vd2⁺ T cells^ref
• vasculopathy leading to cardiac allograft rejection
• lung transplantation chronic rejection
• liver transplantation chronic rejection
• triggers autoantibody formation against CD13 in transplanted patients which, in turn, has been shown to be associated with the development of chronic GvHD
See also the impact of CMV serostatus in allogeneic HSCT
Laboratory examinations :
• IgM (< 0.4 UA/mL => negative; 0.901-0.5 UA/mL => repeat after 10 days; > 0.5 UA/mL => positive)
• IgG (< 15 UA/mL => negative; > 15 UA/mL => positive)
• specific IgG avidity index (AI)^ref
• pp64 antigenemia
• balloon-like CPE, Cowdry type A inclusion bodies, owl-eye inclusions
• ELISA
• DNA fingerprinting
• rapid-flow cytometry T-cell-based approach may represent a reliable alternative for defining CMV status in any clinical situation where serologic testing is limited by borderline titers or by the presence of passively administered antibodies^ref.
• the diagnostic value of the detection of CMV in BAL, which is high in allogeneic BMT recipients with pneumonia and low in patients with acquired immunodeficiency syndrome, has not been determined in autologous BMT recipients^{ref1, ref2}
Therapy :
• antivirals :
• acyclovir is not effective due to lack of tk
• effectiveness of ganciclovir oral chemotherapy (5 mg / kg IV or 1000 mg q8h PO) has been shown in SYNTEX 1654 trial (patients affected by both HIV-1 and CMV). Alternatively 5 mg/kg i.v. twice daily with adjustment for renal function : if resistance occurs (demonstrated by plaque reduction assay or quantitative CMV-DNA hybrid capture assay showing deletions in the UL97 codon range 591-607) =>
• foscarnet (resistance conferred by mutation in the DNA polymerase gene at codon 756 (E-D substitution). However, foscarnet resistance mutations that have been confirmed by marker transfer do not confer crossresistance to cidofovir^{ref1, ref2}.3, 18 )
• cidofovir
• leflunomide alone (induction dose 200 mg/day for 7 days, followed by a maintenance dose of 50 mg/day, targeting a serum level of 60-80 mg/ml of the active metabolite A77 1726)^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8} or in addition to foscarnet^{ref1, ref2} or ganciclovir^ref. Leflunomide is a new disease-modifying antirheumatic drug approved in 1998 in the United States for the treatment of rheumatoid arthritis^ref. Among its proposed mechanisms of action are inhibition of T- and B-cell proliferation by interference with the de novo pathway of pyrimidine synthesis via inhibition of the enzyme dihydroorotate dehydrogenase and inhibition of phosphorylation of specific tyrosine kinases involved in T- and B-cell activity^ref. Leflunomide is increasingly recognized as a potent immunosuppressive agent for the prevention and treatment of rejection in solid organ transplant recipients^ref. It has also been reported to have novel anti-CMV activity in vitro, utilizing a mechanism different from that of other antiviral agents^{ref1, ref2}. The mechanism of leflunomide antiviral activity is a topic of active research, but it does not appear to affect transcription of immediate-early or late viral genes or to inhibit viral DNA polymerase activity. It appears to inhibit virion assembly at a late stage by preventing viral nucleocapsids from acquiring their tegument^ref. As leflunomide does not affect DNA polymerase or other aspects of DNA replication of CMV, it would be expected not to show crossresistance with other agents. One previous anecdotal report suggested a response to leflunomide and cidofovir in a transplant patient with CMV resistant to ganciclovir and foscarnet. Leflunomide also appears to have antiviral activity against HSV as well^ref. Renal compromise may alter the efficacious blood level target^ref and patients with elevated serum creatinine may have substantially reduced protein binding; thus the effective (and toxic) level might be reduced. This has been cited as an explanation for significant variation in active metabolite pharmacokinetic features in a series of patients with chronic renal allograft dysfunction treated with leflunomide^ref
Although ganciclovir has been the mainstay of CMV treatment in the past, ganciclovir-resistant CMV in solid organ and bone marrow transplant recipients has been reported with increasing frequency over the past several years^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8,ref9}. Ganciclovir-resistant CMV has been seen frequently in AIDS patients with CMV retinitis, particularly those receiving lengthy courses of ganciclovir therapy^ref. It is thought that prolonged exposure to ganciclovir, particularly at concentrations that do not fully suppress viral replication, may lead to resistance^{ref1, ref2, ref3, ref4}. Ganciclovir resistance may be assessed by phenotypic analysis by plaque reduction assay^{ref1, ref2} and by genotypic analysis, which demonstrates characteristic mutations in the UL97 region or the DNA polymerase gene^{ref1, ref2, ref3, ref4}. In the past, foscarnet has been the main agent utilized for therapy for ganciclovir-resistant CMV in transplant recipients^ref, but its usefulness in transplant recipients is often limited by nephrotoxicity and electrolyte disturbances. Combination ganciclovir and foscarnet therapy has been utilized in AIDS patients with retinitis (Combination foscarnet and ganciclovir therapy vs monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS. The Cytomegalovirus Retreatment Trial. The Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group. Arch Ophthalmol 1996; 114: 23-33) and in allogeneic stem cell recipients^ref. Recent work suggests that a combination of reduced-dose ganciclovir and foscarnet may be effective and less toxic for ganciclovir-resistant CMV in solid organ transplant recipients^ref. Cidofovir, the third FDA-approved drug for the treatment of CMV^ref, has been used primarily for retinitis in AIDS patients and for CMV in allogeneic stem cell recipients^ref. However, cidofovir is also potentially highly nephrotoxic, and crossresistance between ganciclovir and cidofovir has been described^{ref1, ref2} when mutations occur in the UL54 region^ref. Resistance to foscarnet, to cidofovir, and multiple resistance have been described^{ref1, ref2, ref3, ref4}. A reports described systemic therapy for CMV refractory to all 3 standard drugs^ref

• terminase inhibitors
• homologous immune antiserum. Treatment of pregnant women with primary CMV infection with CMV-specific monthly hyperimmune globulin (100 U/kg i.v.). is safe, and the findings of this nonrandomized study suggest that it may be effective in the treatment and prevention of congenital CMV infection. A controlled trial of this agent may now be appropriate^{ref1, ref2}
Web resources : The World of Human Cytomegalovirus
• Simian cytomegalovirus (SCMV)
=> chronic fatigue syndrome (CFS)
=> encephalopathy (psychoses, ...)
• Roseolovirus
• Human herpesvirus 6A (HHV-6A) / human B-lymphotropic virus (HBLV)

Epidemiology : discovered in 1986^ref; the peak age of acquisition is between 9 and 21 months^ref. In common with other herpes viruses, HHV6 also tends to show persistence and intermittent or chronic shedding in the normal population, making the unusually early infection of children understandable (seroconversion in the first year of life in up to 80% of all children, 90% of children by 2 years of age). This means that HHV6 infections manifesting in close temporal association with recommended vaccinations may be misinterpreted as complications of the vaccination. Today, the situation can be clarified by employing special virological-serological laboratory tests, which are available throughout the country. HHV-6 genome is found in 11% of peripheral blood samples and in 28% of the bone marrow samples from healthy volunteers^ref
Proteomics : glycoprotein H-glycoprotein L-glycoprotein Q complex  binds to CD46 / MCP (expressed ubiquitously in human tissues); it induces syncytium formation of diverse human cells 2 h after infection by fusion from without (FFWO)
=> in immunocompromised individuals :
• fulminant hepatitis
• interstitial pneumonia
• Gianotti-Crosti syndrome (GCS) / papular acrodermatitis of childhood (PAC)
• pityriasis rosea^ref (at a lesser extent than HHV-7^ref), but so far there is not enough evidence for a pathogenetic association of HHV-7 with this exanthematic skin disease^ref. Pityriasis rosea in pregnancy--specific diagnostic implications and management considerations^ref
• lymphoproliferative disorders : HHV-6 activation was documented in 34% of cases of non-Hodgkin's lymphoma (NHL) and 39% of those of Hodgkin's lymphoma; however, no correlation of activation status with pathological types of Hodgkin's disease and between copy numbers in peripheral blood mononuclear cell DNA and the corresponding plasma DNA was noticeable^ref.
• Hodgkin's lymphoma (?)
• Burkitt's lymphoma^ref
• angioimmunoblastic lymphoma
• chronic fatigue syndrome (CFS)
• Langerhans cell histiocytosis (LCH) (?)
• HHV-6 DNA was detected in PBL in 74% of autologous recipients and 76% of allogeneic recipients, and in biopsy tissue in 48% of autos and 71% of allos. However, HHV-6 DNA was detected in skin and/or rectal biopsies more frequently in allogeneic recipients with severe GVHD (92%) than in those with either moderate (55%) or mild GVHD (22%), suggesting an association (P = 0.004) between HHV-6 DNA in biopsy tissue and GVHD severity. A significant linear trend (P = 0.03) was identified between detection of HHV-6 DNA in biopsy tissue obtained prior to or concomitant with the onset of GVHD and increased GVHD severity, suggesting that HHV-6 was causally linked to GVHD rather than reactivated as a consequence of GVHD therapy^ref
It worsens HIV-1 mediated CPE in super-infections of CD4⁺ T-lymphocytes : a 3.9-kbp SalI-L DNA fragment spanning the junction of the direct repeat left (DRL) and unique long segment (UL) regions of HHV-6 up-regulates HIV-1 LTR CAT 10-15 fold in both monkey CV-1 and human T Jurkat cells^ref.
• Human herpesvirus 6B (HHV-6B) / human B-lymphotropic virus (HBLV)

Proteomics : glycoprotein H-glycoprotein L-glycoprotein Q complex  binds to CD46 / MCP (expressed ubiquitously in human tissues); it induces syncytium formation of diverse human cells 2 h after infection by fusion from without (FFWO)
Transmission : older siblings appear to serve as a source of HHV-6 transmission.
=> roseola (infantum) / exanthem or exanthema subitum / rose rash of infants / "sixth" disease (to differentiate it from other exanthems) : an acute, short-lived mononucleosis-like syndrome of infants and young children (expecially between month 6 and age 2) after 5-15 days incubation; after a high fever of 3 to 4 days' duration, occipital lymphadenitis, laterocervical lymphadenitis and retroauricular lymphadenitis the temperature suddenly drops to normal; either shortly before, simultaneously with, or shortly after this happens, a macular or maculopapular rash appears on the trunk and spreads to other areas for 1-2 days.  Downey type III atypical lymphocytes. Complications :
• meningoencephalitis (=> febrile convulsions (with and without exanthem)); usually fatal when it is resistant to antiviral drugs unless treated with donor lymphocyte infusions (DLIs)^ref
• fulminant hepatitis
• lethal disseminated infections
• untypical exanthem or uncharacteristic rash (with and without fever)
• acute respiratory disease (ARD)
• acute gastroenteritis
• complications of ARD (sinusitis, otitis media, bronchial pneumonia)
• Pfeiffer's disease (mononucleosis-like syndrome)
• drug rash with eosinophilia and systemic symptoms (DRESS)
• in individuals with a relevant disposition (genetic HLA/DR type) initiation or (re-)activation of juvenile chronic arthritis (JCA) or chronic iridocyclitis may occur
• HHV-6 promotes the expression of HHV-4 / EBV antigen (may contribute to the pathogenesis of nasopharyngeal carcinoma in cooperation with EBV^ref) and activates lytic cycle replication of HHV-8 / KSHV^ref
Virus undergoes latency => reactivation during immunodepressions => interstitial pneumonia
Roseola occurs in a minority of patients, and febrile seizures are infrequently associated with primary HHV-6 infection
=> Alzheimer's disease (?)
• unclassified Betaherpesvirinae
• Human herpesvirus 7 (HHV-7)
Epidemiology : discovered in 1989^ref. Primary infection occurs early in life. HHV-7 genome is found in 67% of peripheral blood samples and in 50% of the bone marrow samples from healthy volunteers^ref
=> macular-papular rashes in children (exanthema subitum, or other febrile illnesses mimicking measles and rubella.
=> other inflammatory skin disorders, such as psoriasis and papular-purpuric gloves-and-socks syndrome, but has also been found to occur in normal dermal tissues. There are controversial data on the detection of HHV-7 (at a greater extent than HHV-6^ref) in pityriasis rosea^ref (primary infection > reactivation^ref), but so far there is not enough evidence^{ref1, ref2, ref3, ref4}
=> although HHV-7 can be found in some cases of Hodgkin's lymphoma, there are no data supporting a direct causative role in this lymphoma type nor in other nodal or primary cutaneous lymphomas
=> reactivation of HHV-6.
=> in various epidemiologic forms of Kaposi's sarcoma, infection of monocytic cells with HHV-7 was demonstrated, which may indirectly influence tumor biology
=> in the context of immunosuppression, HHV-7 has recently been identified as an emerging pathogen in transplant recipients and may exacerbate graft rejection in renal transplant recipients.
The ability of HHV-7 to induce cytokine production in infected cells could make HHV-7 an important pathogenetic co-factor in inflammatory and neoplastic disorders. Moreover, the restricted cellular tropism of HHV-7 may render this virus an interesting vector for gene therapy^ref
• Gammaherpesvirinae / lymphocyte-associated virus (lymphoproliferative virus group)
• Lymphocryptovirus / gamma-1 herpesviruses
• Human herpesvirus 4 (HHV-4) /  Epstein-Barr virus (EBV) / EB virus
• Rhadinovirus / gamma-2 herpesviruses
• Human herpesvirus 8 (HHV-8) / Kaposi's sarcoma-associated herpesvirus (KSV / KSHV)
• subacute myelo-optic neuropathy (SMON) virus / Inoue-Melnick virus (IMV)
• type I
• type II
Epidemiology : epidemics in Japan (1960's), Cuba (1991-1993) and Tanzania (1988-2003). A possible connection between Tanzania & Cuba may is that the Cuban military were in Tanzania before 1976, not as combatants but as coordinators of Cuban forces fighting in other African countries
=> subacute myelo-optic neuropathy (SMON) : a clinical syndrome affecting the spinal cord, optic nerve, and peripheral nerves, preceded by diarrhea. Symptoms include paresthesia in both lower limbs, gait disturbances, visual disturbances, abnormalities of deep tendon reflexes, and psychic disorders. The hydroxyquinolones (especially clioquinol), taken for gastrointestinal disorders, have been implicated as an etiologic factor
• Papillomaviridae


(reproduced with permission from Nature Reviews Immunology (Vol 4, No. 1, pp 46-55 (2004)) copyright Macmillan Magazines Ltd)
• Papillomavirus : papillomaviruses; a genus of viruses family Papovaviridae that induce papillomas in humans and in many animal species. Papillomaviruses are highly species-specific and have a tropism for squamous epithelium; some have been associated with malignancy
• Human papillomavirus (HPV)
• Human papillomavirus type 1a
=> slaughterers' wart
=> verruca plana / plane wart
=> verruca palmaris or verruca plantaris (myrmecia or palmoplantar wart)
=> verruca vulgaris / common wart
• Human papillomavirus type 2
=> epidermodysplasia verruciformis with macules
=> verruca vulgaris / common wart
=> lip lesions
=> verruca palmaris or verruca plantaris (myrmecia or palmoplantar wart)
=> slaughterers' wart
=> flat condyloma of cervix
• Human papillomavirus type 2a
• Human papillomavirus type 2c
• Human papillomavirus type 3
=> flat condyloma of cervix
=> slaughterers' wart
=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 4
=> verruca vulgaris / common wart
=> verruca palmaris or verruca plantaris (myrmecia or palmoplantar wart)
=> slaughterers' wart
=> flat condyloma of cervix
• Human papillomavirus type 5

=> epidermodysplasia verruciformis
• Human papillomavirus type 5b
• Human papillomavirus type 6
=> anogenital wart / exophytic condyloma / condyloma acuminatum
=> flat condyloma of cervix
=> weak association with cervical carcinoma
=> conjunctival papilloma
=> laryngeal papilloma
=> Heck focal epithelial hyperplasia (?)
• Human papillomavirus type 6a
• Human papillomavirus type 6b
• Human papillomavirus type 6c
• Human papillomavirus type 6e
• Human papillomavirus type 6vc
• Human papillomavirus type 7
=> slaughterers' wart
• Human papillomavirus type 8

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 9

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 10
=> epidermodysplasia verruciformis with macules
=> verruca plana / plane wart
=> slaughterers' wart
=> weak association with cervical carcinoma
• Human papillomavirus type 11
=> laryngeal papilloma
=> conjunctival papilloma
=> Heck focal epithelial hyperplasia (?)
=> epidermodysplasia verruciformis
=> anogenital wart / exophytic condyloma / condyloma acuminatum
=> flat condyloma of cervix
=> weak association with cervical carcinoma
• Human papillomavirus type 12

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 13
=> Heck focal epithelial hyperplasia
• Human papillomavirus type 14
• Human papillomavirus type 14D
=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 15

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 16
Proteomics : E7 gene encodes a multifunctional oncoprotein that can subvert multiple cellular regulatory pathways :
• retinoblastoma tumor suppressor protein pRB
• the related pocket proteins p107 and p130
• 600-kDa retinoblastoma protein associated factor, p600 (independent of the pocket proteins and is mediated through the N terminal E7 domain, which is related to conserved region 1 of the adenovirus E1A protein and importantly contributes to cellular transformation independent of pRB binding)^ref
=> laryngeal papilloma
=> Heck focal epithelial hyperplasia (?)
=> flat condyloma of cervix
=> strong association with cervical carcinoma (cervical intraepithelial neoplasia (CIN)). Higher crude viral load, as determined by RT-PCR targeting the E7 gene, was observed for SCC but became insignificant after normalization for cell content. Integration was located and quantified by real-time PCRs targeting, respectively, the carboxyl, amino, and hinge domains of the E2 gene. Pure episomal, integrated, and mixed forms were observed in all disease groups. Most E2 gene disruptions involved the amino-terminal, but sparing the hinge region that has been frequently used as a surrogate marker of integration. Large-fragment disruption involving all 3 E2 regions was observed only in the CIN 3 and SCC groups. Altogether, 33.3% of the CIN 3 group and 28.0% of the SCC group harbored pure episomal genomes. The Asian lineage was associated with a higher risk for CIN 3/SCC than the European lineage, and 6 of the 7 large-fragment E2 disruptions were from Asian lineage. The link between viral lineage, integration pattern, and oncogenesis deserves further study^ref.
=> vulvar carcinoma
=> penile intraepithelial neoplasia (PIN)
=> bowenoid papulosis
=> in 29% of breast carcinoma and metastatic lymph nodes using PCR^ref; in both breast and cervical cancer tissues in Norwegian women with concurrent breast carcinoma and cervical carcinoma^ref
• Human papillomavirus type 17

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 18

=> flat condyloma of cervix
=> strong association with cervical carcinoma (cervical intraepithelial neoplasia (CIN)). In most cases the immune system knocks the virus out before it can do any damage. In some cases, however, the infection becomes chronic, with measurable levels of the virus remaining in the system. Perhaps 5% of these women will eventually develop precancerous lesions that could lead to cervical cancer. Or at least that's what would happen if they did not undergo routine Pap smears, which can detect abnormal cervical tissue before it turns malignant.
• Human papillomavirus type 19

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 20

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 21

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 22

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 23

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 24

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 25

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 26

=> verruca vulgaris / common wart
=> weak association with cervical carcinoma
• Human papillomavirus type 27

=> verruca plana / plane wart
=> verruca vulgaris / common wart
• Human papillomavirus type 28
=> verruca vulgaris / common wart
=> slaughterers' wart
• Human papillomavirus type 29

=> verruca vulgaris / common wart
• Human papillomavirus type 30
=> laryngeal papilloma
• Human papillomavirus type 31

=> flat condyloma of cervix
=> strong association with cervical carcinoma
• Human papillomavirus type 32
=> Heck focal epithelial hyperplasia
• Human papillomavirus type 33

=> moderate association with cervical carcinoma
=> breast carcinoma of 41% of Chinese and 11% of Japanese women^ref
• Human papillomavirus type 34
• Human papillomavirus type 35
• Human papillomavirus type 35H
=> moderate association with cervical carcinoma
• Human papillomavirus type 36

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 37

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 38

=> epidermodysplasia verruciformis with macules
=> verruca plana / plane wart
• Human papillomavirus type 39

=> penile intraepithelial neoplasia (PIN)
=> moderate association with cervical carcinoma
• Human papillomavirus type 40

=> penile intraepithelial neoplasia (PIN)
=> weak association with cervical carcinoma
• Human papillomavirus type 41

=> verruca vulgaris / common wart
• Human papillomavirus type 42

=> flat condyloma of cervix
=> weak association with cervical carcinoma
• Human papillomavirus type 43

=> weak association with cervical carcinoma
• Human papillomavirus type 44

=> flat condyloma of cervix
=> weak association with cervical carcinoma
• Human papillomavirus type 45

=> strong association with cervical carcinoma
• Human papillomavirus type 47

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 48
• Human papillomavirus type 49

=> wart in transplanted individuals
=> verruca plana / plane wart
• Human papillomavirus type 50

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 51

=> moderate association with cervical carcinoma
• Human papillomavirus type 52

=> moderate association with cervical carcinoma
• Human papillomavirus type 53

=> weak association with cervical carcinoma
• Human papillomavirus type 54

=> flat condyloma of cervix
=> weak association with cervical carcinoma
• Human papillomavirus type 55

=> bowenoid papulosis
• Human papillomavirus type 56

=> moderate association with cervical carcinoma
• Human papillomavirus type 57
• Human papillomavirus type 57b
=> verruca vulgaris / common wart
• Human papillomavirus type 58
=> moderate association with cervical carcinoma
• Human papillomavirus type 59
=> moderate association with cervical carcinoma
• Human papillomavirus type 60
• Human papillomavirus type 61
=> weak association with cervical carcinoma
• Human papillomavirus type 62

=> weak association with cervical carcinoma
• Human papillomavirus type 63

=> verruca palmaris or verruca plantaris (myrmecia or palmoplantar wart)
• Human papillomavirus type 64
• Human papillomavirus type 65

=> verruca vulgaris / common wart
• Human papillomavirus type 66
• Human papillomavirus type 67
• Human papillomavirus type 68
=> moderate association with cervical carcinoma
• Human papillomavirus type 69
• Human papillomavirus type 70
• Human papillomavirus type 71
• Human papillomavirus type 72
• Human papillomavirus type 73
• Human papillomavirus type 74
• Human papillomavirus type 75

=> verruca plana / plane wart
• Human papillomavirus type 76

=> verruca plana / plane wart
• Human papillomavirus type 77

=> verruca vulgaris / common wart
• Human papillomavirus type 80
• Human papillomavirus type 82
• Human papillomavirus type 83
• Human papillomavirus type 84
• Human papillomavirus type 86
• Human papillomavirus type 87
• Human papillomavirus type JC9710
• human papillomavirus type JC9813
• Human papillomavirus type me180
• Human papillomavirus type RTRX7
• human papillomavirus type Xc
• human papillomavirus type Xd
• human papillomavirus type Xf
• human papillomavirus type Xg
• human papillomavirus type Xh
Epidemiology : HPV is a common infection in the general population (about 630 million women worldwide are infected with sexually transmitted HPVs). HPV association with genital warts was discovered in 1907 by the Italian scientist, Ciuffo.
=> 1% of sexually active adults (aged 15-49 years) either have or have had genital warts. In the remaining sexually active population without warts HPV is pervasive with > 50% having subclinical or latent infection. The peak prevalence occurs in men and women aged 17 to 33 years and the peak incidence in those aged 20 to 24 years. HPV is highly infective and a transmission rate after a single encounter has been reported to be as high as 26%. In 10-20% of patients spontaneous resolution of their disease will occur within 3-4 months. Current therapies may have little effect on eradication of HPV or transmission of infection and have recurrence rates of 30-70% within 6 months of end of treatment.
=> all types can also cause subclinical infections and the immune response to the virus protects against chronic infection that can lead to cancer. In a minority of individuals the immune response seems not to be strong enough or of the right type, allowing the establishment of chronic infection.
Genomics :
• human loci
• human papillomavirus (type 18) integration site 2 (HPV18I2) (a heritable fragile site)
• human papillomavirus (type 6a) integration site 1 (HPV6AI2) (contains the site of breakpoints affecting protooncogenes Hox11 and Lyt10)
• human papillomavirus (type 18) E5 central sequence-like 1 (HPVC1)
• papillomavirus regulatory factor (PRF)-1 /papillomavirus binding factor (PBF)  recognizes the sequence CCGG, which represents the 3' half of the E2 binding sites of papillomaviruses which mediate transcriptional repression by E2
• RUNX1 / CBF binds to the repression-mediating E2 binding site P2 of HPV8
• papillomavirus L2 interacting nuclear protein 1 (PLINP-1)
Proteomics : gene expression and vegetative replication occur exclusively in epithelial cells, confined to cells in the upper spinous or granular layers of squamous epithelia. Production of sufficient amounts of viral proteins and virion-assembly takes place only in cells destined eventually for desquamation and death.
• early genes :
• E1 is a DNA helicase that assists episomal replication; it is produced in + amount and has nuclear localization. It interacts with thyroid hormone receptor interactor 13. No natural immune response
• E2 is a transcription factor (nuclear localization) produced in + amounts that regulates HPV gene expression by sequence-specific DNA binding to E2 binding sites or Sp1 binding sites (p21(WAF1/CIP1)). It binds to C/EBP factors and may contribute to enhancing keratinocyte differentiation, which is suppressed by the viral oncoproteins E6 and E7 in HPV-induced lesions. It interacts with topoisomerase (DNA) II binding protein (TOPBP1) and G protein pathway suppressor 2 (GPS2) activating transcription of HPV genes. It targets ADA3 protein for degradation. Cellular responses are associated with regressing lesions in infected animals
• E3
• E5 is produced in + amounts and has cytoplasmic localization. It prevents cell differentiation (more important for BPV than HPV). It impairs TRAIL-mediated apoptosis by impairing DISC formation, and FasL-mediated apoptosis by downregulating Fas expression. No natural immune response
• intermediate genes
• E6 is produced in + amount and has nuclear localization. It prevents cell differentiation and interacts with ubiquitin protein ligase E3A (UBE3A) resulting in ubiquitination and proteolysis of tumor protein p53. It represses IL-8 transcription through effects on CREB binding protein/p300 and P/CAF. It interacts with karyopherin (Kap) a₂ and via its basic nuclear localization signal (NLS) located at the C terminus, with both Kap b₁ and Kap b₂ import receptors. It  targets the MAGI-2 and MAGI-3 proteins for degradation. It binds to tumor necrosis factor (TNF) R1 and protects cells from TNF-induced apoptosis.
• E7 is produced in ++ amount and has nuclear localization. It prevents cell-growth arrest/differentiation by inhibiting inhibitors of E2F transcription factor. Eg LXCXE peptide motif inactivates pRbby binding 3 regions of the pocket domain and inhibits the DNA interaction of the TATA binding protein. DTH is associated with regressing CIN lesions in humans. Antibody associated with invasive cervical cancers in humans
• E8 represses IL-8 transcription through effects on CREB binding protein/p300 and P/CAF
• late genes
• L1 major capsid protein (structural) is produced in ++++ amount and has nuclear localization; antibody in 50-100% of infected humans, occurring weeks to years after infection; HPV11 L1 interacts with Kap b₂ and Kap b₃ nuclear import receptors
• L2 minor capsid protein is produced in ++ amounts and has nuclear localization assisting packaging of DNA; mRNA translation is controlled by poly(rC) binding protein 1 (PCBP1) and and PCBP-2; no natural immune response
• E4 is produced in +++ amount and has cytoplasmic localization, assisting packaging of virus (?). No natural immune response
Why human papillomavirus is a poor natural immunogen :
• HPV is a dsDNA virus with no dsRNA intermediate to einvoke innate immune responses
• HPV mainly encodes non-secreted nucleoproteins, which are not effectively cross-presentede by infected cells
• most viral non-structural proteins are expressed at low levels compared with more immunogenic proteins from other viruses
• the virus only infects epithelial cells - an anti-inflammtory environment (IL-10 and TGF-b predominate)
• infection induces cell proliferation rather than cytolysis, without danger signals or antigen release to invoke innate immunity
• infection has no viraemic phase, as infected cells do not undergo lysis as a result of infection, and therefore less systemic antigen presentation occurs.
Laboratory examinations :
• electron microscopy. Only applicable in benign lesions as in malignant lesions the viral DNA is integrated and viral particles are not produced.
• IHC can detect major capsid protein but are generally group specific not type specific
• PCR : at present the only commercial test available is the Hybrid Capture^TM test which will differentiate between oncogenic and non-oncogenic HPV infections.
Prevention :
• subunit vaccines
• topical microbicides : carrageenan, an inexpensive, widely available compound extracted from red algae and used as a thickening agent in everyday products such as toothpaste and yoghurt, is highly effective at preventing the spread of the sexually transmitted HPV. The cheap ingredient was found to be effective at a concentration 100 times lower than the best HPV inhibitor currently on the market. Carrageenan was already known to be an inhibitor against the AIDS-causing virus HIV, and is currently undergoing clinical trials for that. The compound is also already used in a variety of sexual lubricants because of its gelling properties. Some of these over-the-counter products are decidedly effective against HPV transmission in the test-tube. The exciting thing is it is already available in various lubricants. The compound is easy to come by, and is classed as "generally regarded as safe" by the US Food and Drug Administration. Carrageenan, Irish for 'moss of the rock', is produced by boiling red seaweeds found in abundance along the rocky coasts of North America and Europe. Carrageenan acts like a border control, sticking to proteins on the HPV and preventing the virus from interacting with, or entering, the cells of the cervix. It seems to have a protective effect with some other viruses too, including the cold-sore-causing HSV. But HSV has an extra protective membrane that makes it less susceptible to carrageenan; a dose a thousand times greater was needed to achieve equivalent protection against HSV as was achieved against HPV. If carrageenan were added to an HIV microbicide, it could form one of the best preventatives against sexually transmitted diseases available. > 5,000 women in South Africa are currently taking part in phase 3 clinical trials of Carraguard, a vaginal gel containing carrageenan that has been designed to protect against HIV. These trials are due to end in 2007. Further trials will be designed to explicitly test the compound's effectiveness against HPV transmission. They are also working on developing a mouse model of HPV so that they can study it more closely in the lab^ref.
Therapy : for cutaneous warts, for genital warts
• [Papovaviridae : the papovaviruses: a family of DNA viruses having a nonenveloped icosahedral virion 40 nm (polyomaviruses) or 55 nm (papillomaviruses) in diameter with 72 capsomers in skew arrangement. The genome consists of a single circular molecule of double-stranded DNA (MW 3–5 ´ 106, size 5 kbp for polyomaviruses and 8 kbp for papillomaviruses). Viruses contain five to seven structural proteins and are resistant to ether, acids, and heat. Replication and assembly occur in the nucleus; virions are released by cell destruction. Host range is generally narrow; transmission is by contact or by airborne particles, and many species are oncogenic. There are 2 genera, Papovavirus and Polyomavirus]
• Polyomaviridae
• Polyomavirus: polyomaviruses; a genus of viruses of the Papovaviridae that induce tumors in experimental animals
Epidemiology : the polyomaviruses tend to have restricted host ranges, although cells which fail to support virus replication may become genetically transformed via the action of early gene products. In general, the polyomaviruses spread by reactivation of persistent infections in the mother during pregnancy, with low level shedding of virus in urine. The polyomaviruses often exhibit highly specific tissue-specific expression with frequent involvement of the kidney. human polyomaviruses are ubiquitous and exhibit a sero-prevalence of 60 to 80% in adults, but clinically relevant infections due to CPE on urothelium and epithelium are usually limited to individuals who are immunosuppressed
Pathogenesis : following a primary infection via the respiratory tract in childhood, these viruses are diffused in the blood using the B-lymphocytes during their latent stage in the urogenital tract. The reactivation that occurs after several years is asymptomatic and urinary excretion of BKV is observed in 4 to 6% of immunocompetent patients. They are mutagenic^ref. Sialic acid plays in determining viral tropism^ref.

• African green monkey polyomavirus
  
• BK polyomavirus (BKV)
• BK virus strain AS
• BK virus strain GS
Epidemiology : seroprevalence rises significantly from 64% in 1-4-year-old children to 91% in 5-9-year-olds; titres decreasing linearly at a rate of 8.7% per 10 years^ref
Proteomics :
• receptor : BKV uses the terminal a2-8-linked disialic acid motif of gangliosides GT1b and GD1b as receptors and passes through the ER on the way to the nucleus^ref
Transmission : polyomaviruses are frequently present in stool samples from hospitalized children, suggesting that fecal-oral transmission of BKV may play a role in the ubiquity of infection^ref
=> tubulointerstitial nephritis (polyomavirus-associated neprhopathy (PVAN)) and ureteral stenosis in renal transplant recipients
=> hemorrhagic cystitis (HC) in bone marrow transplantation recipients. Architectural rearrangements in the non-coding control region (NCCR) of BKV did not appear to be a prerequisite for development of hemorrhagic cystitis in HSCT recipients^ref. C to G point mutations, within the BKV NCCR Sp1 binding site, were significantly more common in patients with HC, suggesting that these mutations may be indicative for the clinical diagnosis of HC and could influence the virulence of the virus^ref.
=> in episomal state, generally in a low copy number (0.2 to 2 genome equivalents per cell). :
• 44% of islet cell cancers^ref (including insulinoma^ref)
• 25.6% human brain tumors^ref
• 11 of 24 brain tumors of 11 different types^ref
There are increasing reports of BKV causing PVAN and HC in non-renal SOT recipients and other immunodeficiency diseases. This might be related to the use of more potent immunosuppressive regimens or increasing awareness of BKV as an important pathogen
Laboratory examinations : PCR in blood or biopsy, BKV nuclear inclusions can be seen
Therapy : reduction of immunosuppression, cidofovir
• JC virus (JCV)
• simian virus 40 (SV40)
• unclassified Polyomavirus
• JC virus x BK virus
• K virus : a nononcogenic virus of the genus Polyomavirus that produces fatal interstitial pneumonia on inoculation into newborn mice
• KI polyomavirus is phylogenetically related to other primate polyomaviruses in the early region of the genome but has very little homology (<30% amino acid identity) to known polyomaviruses in the late region. The virus was found by PCR in 6 (1%) of 637 nasopharyngeal aspirates and in 1 (0.5%) of 192 fecal samples but was not detected in sets of urine and blood samples^ref. When 951 respiratory samples collected in Queensland, Australia, between November 2002 and August 2003 from patients with respiratory infection, were tested for the presence of the KI virus, 24 (2.5%) samples were positive for KI virus with 20 (83%) of these from children younger than 5 years. In 6 (25%) patients KI was co-detected with another virus. Full genome sequencing of three isolates shows a high degree of conservation between the Queensland isolates and the original isolates reported from Swedish patients^ref
• Merkel cell polyomavirus (MCV) was identified in Merkel cell carcinomas (MCC) using digital transcriptome subtraction^ref and later found in folliculotropic mycosis fungoides^ref
  
• WU Polyomavirus : initially detected in a nasopharyngeal aspirate from a 3-year-old child from Australia diagnosed with pneumonia. Screening of 2,135 patients with acute respiratory tract infections in Brisbane, Queensland, Australia, and St. Louis, Missouri, United States, using WU virus-specific PCR primers resulted in the detection of 43 additional specimens that contained WU virus^ref
• STL polyomavirus (STLPyV) : in clinical stool specimens from USA and The Gambia at up to 1% frequency^ref; common exposure during childhood^ref
  
• Polyomavirus HPyV6 : in 2010, discovered on the foreheads of healthy volunteers
  
• Polyomavirus HPyV7 : in 2010, were discovered on the foreheads of healthy volunteers
• Human polyomavirus 9 (HPyV9) : in blood of 21% renal transplant recipients^ref; positivity rates peaked at 3 months after transplantation, but the highest viral loads were measured just after transplantation. During 18 months of follow-up, HPyV9 seroprevalence increased from 33% to 46% among transplant patients; seroprevalence remained stable at ≈30% in a control group of healthy blood donors in whom no HPyV9 DNA was detected. Further analysis revealed an association between detection of HPyV9 and detection of BK polyomavirus but not of cytomegalovirus^ref.
  
• Human polyomavirus 12
• Trichodysplasia spinulosa-associated polyomavirus (TSPyV) was isolated in 2010 from the face of an immunocompromised patient suffering from Tricodysplasia spinulosa. This condition is found exclusively in immunocompromised patients and leads to numerous follicular extensions around the face and nose.
• Malawi polyomavirus (MWPyV) was identified in 2012 in a stool sample of a healthy child
• New Jersey polyomavirus (NJPyV-2013) is a novel polyomavirus that may have tropism for vascular endothelial cells, isolated in 2014 from a pancreas transplant recipient with myositis and cutaneous necrosis^ref
  
• HPyV10 was isolated in 2013 from condylomas on the buttocks of patients suffering a rare genetic disorder known as warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome
• MXPyV, like MWPyV, was identified in 2013 in stool samples from children suffering diarrhea in Mexico.
  
• Poxviridae: the poxviruses: a family of DNA viruses having a brick-shaped or ovoid virion 220–450 x 140–260 nm consisting of an envelope containing lipid and tubular or globular protein structures surrounding a DNA-containing core and one or two lateral bodies. The genome consists of a single molecule of double-stranded DNA (size 130–375 kbp). Viruses contain over 100 proteins; some are ether-resistant while others are ether-sensitive. Replication and assembly occur in the cytoplasm; virions are released by cell destruction or budding. Host range is narrow and transmission is by fomites, airborne particles, arthropod vectors, or contact. There are 2 subfamilies :
• Entomopoxvirinae (which includes 3 genera of poxviruses infecting invertebrates)
• Chordopoxvirinae (poxviruses of vertebrates, causing zoonoses^ref)
• Avipoxvirus
• fowlpox virus
=> Bollinger bodies
• Capripoxvirus comprising the sheeppox, goatpox, and lumpy skin disease viruses.
• Leporipoxvirus infect squirrels and rabbits, including myxoma virus and rabbit fibroma virus.
=> T2 proteins are TNFRII-like decoys
• Molluscipoxvirus
• Molluscum contagiosum virus (MCV)
• Molluscum contagiosum virus subtype 1
• Molluscum contagiosum virus subtype 2
• Molluscum contagiosum virus subtype 3
Epidemiology : it occurs worldwide, but is much more frequent in certain areas like Zaire and Papua New Guinea. It is seen most commonly in children
Proteomics : binding of FADD and caspase-8 to MC159 v-FLIP (which inhibits Fas-, TNF-, and TRAIL-induced apoptosis) is not sufficient for its antiapoptotic function
Transmission : direct bodily contact, through minor abrasions, or indirectly via fomites (swimming pools, ...) : among young adults, it is usually a STD.
Proteomics :
• MC148, a CCR8-like decoy receptor
Large hyaline acidophilic granular masses known as Henderson-Peterson's bodies / molluscum bodies fill the cytoplasm and push the nucleus to the edge of the infected cells.
=> molluscum contagiosum
• Orthopoxvirus (OPV)
• Aracatuba virus (a.k.a. Araçatuba virus)
Epidemiology : Minas Gerais state, Brazil
=> cowpoxlike outbreak in a dairy herd (nodular and pustular lesions on bovine teats, frequently related to viral infections such as bovine herpes mammillitis, pseudocowpox, and cowpox infections) and a related case of human infection in hand of dairy farm worker (milker). Diagnosis was based on virus growth characteristics, electron microscopy, and molecular biology techniques. Molecular characterization of the virus was done by using polymerase chain reaction amplification, cloning, and DNA sequencing of conserved orthopoxvirus genes such as the vaccinia growth factor (VGF), thymidine kinase (TK), and hemagglutinin. Gene sequences showed 99% homology with vaccinia virus genes and were clustered together with the isolated virus in the phylogenetic tree. Aracatuba virus is very similar to Cantagalo virus (could represent its spread), showing the same signature deletion in the gene^ref
• Camelpox virus (CMLV)
Epidemiology :
Genomics : among OPVs, CMLV is the most closely related to variola virus (96% amino acid identity), sharing all genes involved in basic replicative functions and the majority of genes involved in other host-related functions. 27 CMLV ORFs are absent in variola virus, including 7 full-length homologues of NMDA-like receptor, PL-D, Schlafen, MT-4 virulence, kelch, vaccinia virus C8L, and cowpox virus B21R proteins. 38 CMLV ORFs, some of which are fragments of larger genes, differ in size from corresponding VARV ORFs by more than 10% (amino acids). As it has been suggested for VARV, it may have originated from a cowpox virus-like ancestor.
=> camelpox, a disease which exclusively affects Camelidae: clinical manifestations vary from a singular pox lesion to a generalized form, with pox literally covering the entire animal and even found on internal organs (e.g. lungs)
Prognosis : mortality may reach 30%, and complications due to secondary bacterial and mycotic infections are common. Severe cases of camelpox to the point of fatality have been described in camels from Saudi Arabia after they have been exported to the UAE^ref.
Differential diagnoses include: 1. papillomatosis, the warts of which may be taken as pox lesions after secondary bacterial infection, but they are usually smaller, and 2. contagious ecthyma caused by Pseudocowpox virus, a member of the genus Parapoxvirus. Pox induced through an infection with the latter cannot be clinically distinguished from pox caused by camelpoxvirus. Lumpy skin disease (LSD, caused by another poxvirus which belongs to another genus, Capripoxvirus, with the better-known members Sheeppox virus and Goatpox virus) has not been described on the Arabian peninsula yet  Until 1988, it was restricted to sub-saharan Africa, but it is now known in Egypt^ref. LSD does infect cattle and displays a clinical picture resembling pox, but the host range does not include camels. On the other hand, the host range of camelpox is restricted to Old World camelids (New World camelids are susceptible to the infection, but the natural occurrence of camelpox is restricted to the Old World - with the exception of Australia). Hence, camelpox is unlikely to be the cause of the observed disease in cows. To cut this short; if the described pox-like disease in camels and cows is indeed caused by the same etiological agent, pseudocowpox virus would be a possible but very surprising candidate, because -- at least in cows -- only the udder is usually affected and fatal outcomes are very unusual. Hence, it seems more likely that 2 different viruses are at work: one causing the pox in camel and the other responsible for the effects seen in cattle. Alternatively, bacterial infection(s) might also be considered. LSD has been recorded and reported in Bahrein (1993, 1994, 2002, 2003); Kuwait (1991); Oman (1994); and the United Arab Emirates (2000). These might have been introductions from Eastern Africa by imported cattle for slaughter^ref.
• Cantagalo virus (CTGV)
Epidemiology : isolated from skin lesions on dairy cows and milkers during recent exanthem episodes in Cantagalo County, Rio de Janeiro State, Brazil. It is more like vaccinia virus (VV) than cowpox virus. An eruptive moderate form of camelpox^ref. CTGV may have derived from VV-IOC by persisting in an indigenous animal(s), accumulating polymorphisms, and now emerging in cattle and milkers as CTGV. CTGV may represent the first case of long-term persistence of vaccinia in the New World^ref
• Cowpox virus (CWXV / CPXV))
• Cowpox virus (strain Turkmenia-1974)
• Cowpox virus (strain Hamburg-1985)
Epidemiology : found only in Europe and in adjacent parts of the former USSR. Despite its name, the reservoir hosts of cowpox virus are Rodentia, from which it can occasionally spread to Felis catus, Canis familiaris, Bos taurus, and zoo animals, including large cats and elephants.
Transmission to humans has traditionally occurred via contact with the infected teats of milking cows : however, currently, infection is seen more commonly among domestic cats.
Proteomics :
• cytokine response modifying (Crm) proteins
• crmA inhibits the activation of caspases 1 and 8 and prevents IL-1b and IL-18 processing
• crmB is a p48 secreted p75^TNFRII-like decoy receptor for TNF-a and TNF-b
=> cowpox : 9-10 days incubation => pustules at the site of their introduction into the skin (usually the hands: on the thumbs, the first interdigital cleft, and the forefinger), rarely fever and myalgia => secondary lesions occur only in individuals with immunological deficiencies.
Pathogenesis : greater epithelial thickening, less rapid cell necrosis, and more involvement of the mesodermal tissues than with variola virus
Therapy : VIG should be restricted to the most severe cases. Usually, the lesions regress spontaneously.
ectromelia virus (EV)
Proteomics :
• soluble, secreted receptors for IFN-g and IFN-a/b that are homologous to those identified in other OPVs : anyway vIFN-a/bR is unable to inhibit mouse IFN-b.
• dsRNA-binding protein encoded by an intact homolog of the VV E3L gene.
• no functional K3L gene, which encodes a viral eIF-2a homolog
=> mousepox / infectious ectromelia : a lethal disease of mice characterized by gangrene and often loss of one or more of the feet and sometimes of other external parts, and by necrotic areas in the liver, spleen, and other organs. Introduction of the T_h2cytokineIL-4 gene in ectromelia virus further increases lethality, even in recently immunized genetically resistant mice. These data therefore suggest that virus-encoded IL-4 not only suppresses primary antiviral CMI but also can inhibit the expression of immune memory responses.
monkeypox virus (MPXV)
• Monkeypox virus (strain Sierra Leone 70-0266)
• Monkeypox virus (strain Zaire 77-0666)
Epidemiology : found only in the small villages of the tropical rain forests of western and central Africa, with cases mostly reported in Zaire : only 400 cases were reported worldwide from the time infection by monkeypox virus was first observed in 1970 (in the Democratic Republic of the Congo (DRC) in a region where smallpox had been eradicated in 1968) to 1986.
• Sudan^ref : from 27 Oct 2005 until 18 Nov 2005, 19 cases in Bentiu, Unity State; related to the DRC clade^ref
• Democratic Republic of the Congo (DRC)
• an outbreak of human monkeypox in the between February 1996 and October 1997 was associated with person-to-person transmission; a change from prior limited outbreaks. Previous studies over a 20-year period had shown that the rate of transmission of monkeypox within households was low, suggesting that the disease had a low potential for transmission from person to person. Outbreaks were generally self-limiting after 1-2 sequential transmissions. The percentage of suspect cases from person-to-person transmission (78%) was higher in this outbreak than previously reported (30%) and the proportion of patients that were > 15 years (27%) was higher than previously reported (8%). This was associated with the clustering of cases in household compounds and prolonged chains of transmission from person to person.
• a human monkeypox epidemics in Impfondo (a remote, isolated town of approximately 45 000 people in the center of the Congo Basin Rain Forest, capital of the Likouala Region, which is the northernmost region of the Democratic Republic of Congo (DRC). Impfondo is located on the western banks of the Oubangui River, a major tributary of the Congo River) initiated on 15 Apr 2003 was then discovered on 14 June.
• a monkeypox virus epidemic has been reported near Mbuji Mayi (which is located in the South-Central region of the country). 56 people from Kanama in the Kabinda District, which include 14 children aged < 5 years and 2 of other age groups, have been treated at the Kanama health center, but no deaths have been reported.
• Kasai Occidental province : several people suffered from monkeypox during Aug-Oct 2006 in Kananga ^ref
• USA : since May 16 to July 8 2003, 71 possible cases (35 laboratory-confirmed) have been reported  :
• 39 in Wisconsin (14 laboratory-confirmed in people as young as 4 and as old as 48)
• 16 in Indiana (7 laboratory-confirmed)
• 12 in Illinois (8 laboratory-confirmed)
• 2 in Missouri (laboratory-confirmed)
• 1 in Ohio
• 1 in Kansas (laboratory-confirmed)
The median age was 28 years (range: 1 to 51 years). The outbreak has been caused by to Utah prairie dogs (Cynomys parvidens) sold from a suburban pet distributor (Phil's Pocket Pets) in Villa Park, Chicago, Illinois, USA. That distributor had a giant Gambian rat (Cricetomys emini), indigenous to African countries, that may have infected batches of prairie dogs. Of the 50 Gambian rats (among > 800 small mammals of 9 different species, including 6 genera of African Rodentia : rope squirrels (Funisciurus spp.), sun or tree squirrels, (Heliosciurus spp.), Gambian giant rats, brushtail porcupines (Atherurus spp.), dormice (Graphiurus spp.), and striped mice (Hybomys spp.)) imported from Ghana in the early April shipment, 10 died en route to the Texas distributor or shortly after arrival, one died later at the distributor's premises, 5 were shipped to a pet store within Texas, 9 remain alive at the distributor's premises, and from 18 to 25 of the rats were sent to Evelee Prokes, owner of the Menagerie Hill Farm in Cincinnati, Iowa, with 18 of those sent from Iowa to the Illinois dealer. The shipment contained approximately 800 small mammals of 9 different species that might have been the actual source of introduction of monkeypox. Of the 5 sold to the pet store in Texas, one was sold to an individual. Authorities said the animal and the owner are fine. The other 4 died. Officials said it is not unusual for deaths to occur in wild animals brought into captivity and that the deaths cannot be assumed to have been caused by monkeypox. TDH officials are hopeful that testing of the live Gambian rats remaining at the distributor's premises and of a dead Gambian rat from the pet store that had been kept frozen may offer additional clues in the ongoing multi-state investigation. Texas officials also said that while the prairie dogs sold by the dealer in Illinois are believed to have come from a Texas distributor, it is not the same dealer who supplied the Gambian rats. They said it does not appear that the prairie dogs and Gambian rats were ever in the same facility in Texas. All patients have had contact with animals; however, at least 2 patients also reported contact with another patient's lesions or ocular drainage. A total of 51 patients reported direct or close contact with prairie dogs, and 1 patient reported contact with a Gambian giant rat. One patient had contact with a Oryctolagus cuniculus that became ill after exposure to an ill prairie dog at a veterinary clinic. No patients have died and 26% patients have been hospitalized, including a child aged <10 years with encephalitis (requiring hospitalization for 14 days) and second child exposed to 3 ill prairie dogs, hospitalized with profound painful cervical and tonsillar adenopathy and diffuse pox lesions, including lesions in the oropharynx. Although the child had difficulty breathing and swallowing, mechanical ventilation was not required. The date of onset for the last case was 20 Jun 2003^ref. Studies indicate that West African and Congo basin isolates of monkeypox virus (MPXV) are genetically distinct. Congo basin MPXV-ZAI-V79 is more virulent for cynomolgus monkeys as compared to presumed West African MPXV-COP-58. This finding may explain the lack of case-fatalities in the U.S. 2003 monkeypox outbreak, which was caused by a West African virus. Virulence differences between West African and Congo basin MPXV are further supported by epidemiological analyses that observed a similar prevalence of antibodies in non-vaccinated humans in both regions, while > 90% of reported cases occurred in the Congo basin, and no fatal cases were observed outside of this region. To determine the basis for this difference in virulence, the genomes of one human West African isolate, and 2 presumed West African isolates were sequenced and compared the sequences to Congo basin MPXV-ZAI-96-I-16. The analysis identified D10L, D14L, B10R, B14R, and B19R as possible virulence genes, with D14L (ortholog of vaccinia complement protein) as a leading candidate^ref. Unpublished experiments Army researchers had done in the 1990s on such viruses in monkeys as part of an effort to find ways to test new smallpox vaccines showed monkeys infected with the West African strain got only mildly ill and none died. 5 out of 6 of those given the other strain got severely ill and all 3 that got the higher dose of it died.
Genomics : 15 genes are carried by smallpox but not by monkeypox. Determination of the complete sequence of the genome of monkeypox virus, however, has indicated that monkeypox virus lacks some of the immunomodulatory genes possessed by smallpox virus, which suggests that monkeypox virus is unlikely to become endemic in the human population. The probability of monkeypox virus mutating into variola virus is likely to be remote.
Transmission : a rare zooanthroponosis from monkeys (which are affected only by mild, epidemic exanthematous disease) and some Rodentia (African tree squirrels (Heliosciurus and rope squirrel (Funisciurus anerythrus)), degu (Octodon degus), Oryctolagus cuniculus) via small lesions on the skin or oral mucous membranes. Person-to-person transmission by respiratory route accounts for < 33% of observed cases : this makes identification and containment much more accessible and the secondary attack rate is low. Nonetheless, the fear has been expressed that monkeypox might evolve to become an endemic human infection
=> monkeypox : 1-31 days (median : 12 days) incubation => features are almost indistinguishable from those of ordinary-type smallpox (generalized pustular rash, fever, and toxemia) with the exception of a greater degree of cervical and inguinal lymphadenitis(47%), including fever preceding or accompanying the onset of a generalized papular rash on the head, trunk, and extremities (73%; typically progressing through stages of vesiculation, pustule, umbilication, and encrustation. Early lesions become ulcers in some patients : many patients had initial and satellite lesions on palms, soles, and extremities. Rashes are generalized in some patients); respiratory symptoms (64%), lymphadenitis , and sore throat (33%). The virus first localizes in mononuclear phagocytic cells, is released into the bloodstream, and then localizes again in skin cells. It also has a healing period that progresses more rapidly than smallpox, but anyway still significant morbidity and mortality (1-10%, with the highest rates among young children).
Laboratory examinations :
• the clinical diagnosis of monkeypox is not so easy, and chickenpox can be mistaken for monkeypox. Moreover, varicella (chickenpox), which is considered as an ordinary mild disease, can wear a very different clinical aspect and even be a fatal disease for an immunodepressed organism. In DRC, the prevalence rate of HIV is quite high
• real-time PCR^ref
Prevention : attenuated vaccine has 85% prevention rate
Therapy : the effectiveness of (1) post-exposure smallpox vaccination and (2) antiviral treatment with either cidofovir or with a related acyclic nucleoside phosphonate analogue (HPMPO–DAPy) were compared after lethal intratracheal infection of cynomolgus monkeys (Macaca fascicularis) with monkeypox virus (MPXV). Initiation of antiviral treatment 24 h after lethal intratracheal MPXV infection, using either of the antiviral agents and applying various systemic treatment regimens, resulted in significantly reduced mortality and reduced numbers of cutaneous monkeypox lesions. In contrast, when monkeys were vaccinated 24 h after MPXV infection, using a standard human dose of a currently recommended smallpox vaccine (Elstree-RIVM), no significant reduction in mortality was observed. When antiviral therapy was terminated 13 days after infection, all surviving animals had virus-specific serum antibodies and antiviral T lymphocytes^ref.
• Vaccinia virus (VACV)
• Vaccinia virus (strain Ankara)
Used as transfection vector.
• Vaccinia virus (strain Copenhagen)
• Vaccinia virus (strain Dairen I)
• Vaccinia virus (strain IHD-J)
• Vaccinia virus (strain L-IPV)
• Vaccinia virus (strain LC16M8)
• Vaccinia virus (strain LC16MO)
• Vaccinia virus (strain Lister)
• Vaccinia virus (strain LIVP)
• Vaccinia virus (strain Tian Tan)
• Vaccinia virus (strain WR 65-16)
• Vaccinia virus (strain Western Reserve (WR))
=> a 40-year-old Caucasian male who had been vaccinated against smallpox at 1 year old and again when 10 years old developed vesicles that gradually turned into raised, dark nodules (as similar to those that develop during cowpox infection) on a finger on each hand after working in lab with very high concentrations of recombinant WR containing an inactivated form of the human gene for cytohesin-1, which could impair the local immune response in the skin by interfering with leukocyte adhesion^ref
• Vaccinia virus (strain Wyeth)
Epidemiology : since 1999, an increasing number of exanthemous outbreaks affecting dairy cattle and cow milkers in Brazil have been reported (Araçatuba virus^ref, Cantagalo virus^{ref, ref}). Since 1963, all Brazilian orthopoxvirus isolates have been characterized as VACV strains^{ref1, ref2, ref3, ref4}. The growing geographic distribution of these outbreaks indicates that these viruses may be emerging as zoonotic pathogens of cattle. This fact is especially important because a growing human population has no vaccine-derived immunity to smallpox or other orthopoxviruses. This situation could create an opportunity for these viruses to disseminate in Brazil. In addition, the isolation of another VACV strain (Passatempo virus) during an outbreak that emerged in March 2003 in the town of Passa-Tempo, Minas Gerais State, Brazil, strengthens the hypothesis that VACV is circulating in the New World and that these viruses seem to be endemic of this region^ref.
It is not known whether vaccinia virus is the product of genetic recombination, or if it is a species derived from buffalopox virus > cowpox virus or camelpox virus or variola virus by prolonged serial passage, or if it is the living representative of a now extinct virus (horsepox).
Proteomics :
• A44L is a 3b-hydroxysteroid dehydrogenase (3b-HSD) which promotes corticosterone synthesis leading to immunosuppression
• A46R and A52R block TLRs and IL-1R signal transduction.
• B1R kinase is ortholog to human Vaccinia related kinase 1 (VRK1), VRK2, and VRK3
• E3L inhibits PKR
• SalF2R encodes a protein related to C-type animal lectins
• SalF7L encodes an active 3b-hydroxysteroid dehydrogenase
• SalF17R
• SalF16R encodes a TNFR
• Vaccinia-virus complement-regulator protein (VCP) is a co-factor for factor I-mediated degradation of both C3b and C4b.
• VH1 phosphatase is ortholog to human DUSP1, DUSP3, and DUSP8.
• thymidylate kinase
• VHR, a Vaccinia virus VH1-related dual-specific protein phosphatase, is phosphorylated at Y138 by ZAP-70.
• DNA ligase
• profilin
• SOD
• part of guanylate kinase
• 2 vaccinia virus genes encoding glycoproteins of the outer envelope of extracellular enveloped virus are conserved in variola virus and this homology is likely to have contributed to the immunological protection which vaccinia virus evoked against smallpox.
Grb2 and Nck1 act cooperatively to promote actin-based motility of vaccinia virus
=> no natural host known
=> 40-60% of infected mice develop viremia and die : with IL-4 gene added the mortality is 100%.
Attenuated strains are used for anti-Orthopoxvirus vaccine.
• Variola virus (VARV)
• During 2013, cutaneous lesions developed in two men in the country of Georgia after they were exposed to ill cows. The men had never received vaccination against smallpox. Tests of lesion material with the use of a quantitative real-time polymerase-chain-reaction assay for non–variola virus orthopoxviruses were positive, and DNA sequence analysis implicated a novel orthopoxvirus species. During the ensuing epidemiologic investigation, no additional human cases were identified. However, serologic evidence of exposure to an orthopoxvirus was detected in cows in the patients’ herd and in captured rodents and shrews. A third case of human infection that occurred in 2010 was diagnosed retrospectively during testing of archived specimens that were originally submitted for tests to detect anthrax. Orthopoxvirus infection should be considered in persons in whom cutaneous lesions develop after contact with animals^ref
  
A comparison of the sequences of 21 different poxviruses revealed the 90 essential genes that equip the viruses to infect and multiply in cells^ref.
Prevention : variolation => anti-Orthopoxvirus attenuated vaccine
Therapy : cidofovir
• Parapoxvirus
• Auzdyk disease virus [camels & sheep?]
• bovine papular stomatitis virus
=> papular stomatitis : a zooanthroponosis (reservoir : Bos taurus)^{ref1, ref2}
• camel contagious ecthyma
• Chamois contagious ecthyma virus
• orf virus / contagious pustular dermatitis virus / ecthyma contagiosum virus
Epidemiology : worldwide, most common in late summer, fall, and winter on pasture, and in winter in feedlots
Pathogenesis^ref
Transmission : a zooanthroponosis through contact with infected reservoir (Ovis aries, Capra hircus, Ovibos moschatus moschatus, Rangifer tarandus, Rupicapra rupicapra, deer^ref) ; indirect infections through contaminated knives or meat have been reported. Transmission of orf virus to humans occurs after contact with infected or recently vaccinated animals and/or fomites in conjunction with skin trauma. Orf virus vaccine strains have been known to cause outbreaks among sheep^ref, and 3 of the illnesses described in this report occurred soon after vaccination of the flock. Veterinary vaccines for orf virus use non-attenuated, live virus preparations and are intended to produce controlled infections in flocks (De la Concha-Bermejillo A, Ermel RW, Zhang MZ, Guo J. Contagious ecthyma (orf) virulence factors and vaccine failure. In: Proceedings of the United States Animal Health Association; Richmond, VA: United States Animal Health Association; 1999). Recently vaccinated animals pose an occupational risk to humans^ref. Orf virus infection is facilitated by skin trauma^ref, and previous case series have associated skin trauma with orf virus infection^ref. Trivial injury (e.g., pricks from thistle) or substantial trauma (e.g., bites) can facilitate transmission of orf virus. Therefore, barrier protection (e.g., nonporous gloves) and hand washing during the care of sheep and goats is recommended whenever feasible. These measures are especially important for any person with a compromised immune system or a chronic skin disorder (e.g., eczema) who has contact with overtly infected animals. Immunocompromised persons should discuss the risks of handling orf-infected animals and infection-prevention strategies with their primary-care physicians. Human orf virus infection is a common yet preventable consequence of contact with sheep and goats. Persons who are most likely to be exposed to orf virus (e.g., farm workers) might be familiar with the infection and thus might not seek medical attention. As a result, clinicians might not be familiar with orf virus infections, leading to a delay in diagnosis and unnecessary antibiotic use. Public health personnel should be cognizant that orf virus infection is similar in appearance and risk factors to life-threatening infections such as cutaneous anthrax and that skin trauma is a predisposing factor to infection.
=> in reservoirs (scabby or sore mouth / contagious ecthyma or pustular dermatitis / orf) : erythematous vesiculopustular eruption on-wool-bearing areas, especially the lips and oral mucosa of young animals, the lesions of which may coalesce and crust over. The proliferative lesions may occasionally occur on the teats and, more seldom on the coronary bands of the feet of sheep and goats. During the course of the disease (1-4 wks), the scabs drop off and the tissues heal without scarring. During active stages of the infection, the more severely affected lambs fail to eat normally and lose condition. Extensive lesions on the feet lead to lameness. Mastitis may result in ewes with lesions on the udder.
=> in humans (occasionally affected) : orf / contagious pustular dermatitis / ecthyma contagiosum.
Differential diagnosis : resemble skin lesions associated with potentially life-threatening zoonotic infections such as tularemia, cutaneous anthrax, and erysipeloid (CDC. Human orf mimicking cutaneous anthrax---California. MMWR 1973;22:108); therefore, rapid and definitive diagnosis is critical. Tularemia and erysipeloid are generally associated with exposure to rabbits or New World sylvan rodents and swine, respectively. Both orf virus infection and naturally acquired anthrax in humans can result from exposure to domestic sheep and goats; thus, exposure history alone (i.e., animal contact) is insufficient to indicate etiology, necessitating laboratory evaluation. Histopathologic features include intraepithelial ballooning and intracytoplasmic inclusions^ref; however, these findings are suggestive and not pathognomonic. Negative-stain electron microscopy can confirm a parapoxvirus infection by demonstrating classic ovoid cross-hatched virions but cannot distinguish orf virus from other parapoxviruses such as paravaccinia (pseudocowpox) virus; serologic testing has the same limitation. Only PCR can definitively identify a parapoxvirus as orf virus. 2 assays have been used by CDC: standard PCR^ref and real-time PCR, which is nearly 1000 times more sensitive^ref. These assays are ideally performed on frozen tissue specimens, vesicle material, or scab debris.
Therapy : self-limiting in hosts with normal immune systems, while immunocompromised patients can have progressive, destructive lesions requiring medical interventions such as cidofovir^ref and surgical debridement^ref.
• pseudocowpox virus / paravaccinia virus / milker's nodule virus (MNV)
=> nodular lesions similar to those of cowpox and orf on the udders and teats of milk cows and the oral mucosa of suckling calves
=> milker's nodule : a zooanthroponosis (reservoir : Bos taurus during milking
• sealpox virus
Transmission : ^ref, captive grey seals (Halichoerus grypus)^ref
• Suipoxvirus
• swinepox virus (SWPV)
Genomics :
• IFN-g receptor
• IFN resistance protein
• IL-18 binding protein
• IFN-a/b binding protein
• extracellular enveloped virus host range protein
• dUTPase
• hydroxysteroid dehydrogenase
• SOD
• serpin
• herpesvirus MHC inhibitor
• ectromelia virus macrophage host range protein
• myxoma virus M011L
• variola virus B22R
• 4 ankyrin repeat proteins
• 3 kelch-like proteins
• 5 vaccinia virus (VV) A52R-like family proteins
• 2 GPCRs
=> swinepox.
• Yatapoxvirus
• Tanapox virus (TPV)
First seen among individuals in the flood plain of the Tana River in Kenya during 2 epidemics (1957 and 1962) of acute febrile illness accompanied by localized skin lesions. Human tanapox has been mostly documented in Kenya and Zaire, but it is believed to occur much more widely throughout tropical Africa.
=> tanapox (most likely a zoonosis transmitted from monkeys or another reservoir host  by infected arthropods; only 1 case of human to human transmission has been reported) : fever during 3-4 days incubation => severe headache and backaches, itching erythema with central thickening of the prickle cell layer => papule which gradually enlarges to reach a maximum Ø of ~ 15 mm by the end of the second week of infection (regional lymphadenitis from about the 5^th day following the appearance of the skin lesion) => ulcers during the third week => gradually heals within 5 to 6 weeks, leaving a scar. In Kenya, the lesions were almost always solitary and were found on the upper arm, face, neck, and truck ; conversely, in Zaire, 22% of patients had multiple lesions (usually 2 or 3, maximum 10), mostly found on the lower limbs, with a couple of patients reporting lesions on the upper limbs, trunk, and head. The virus is much slower in replication than vaccinia virus, with most of the mature progeny is retained inside the cell.
Laboratory examinations :
• laboratory tests not capable of discriminating smallpox from vaccinia, monkeypox, or cowpox
• TEM
• light microscopy after H&E staining^ref :
• A-type inclusion bodies
• B-type inclusion bodies / Guarnieri's bodies or corpuscles
• gel diffusion test : vesicular fluid from a pox lesion incubated with vaccinia hyperimmune serum, constitutes a rapid and inexpensive method when microscopy is not available^ref
• antiorthopoxvirus IgM
• differentiation among orthopoxviruses
• isolation of the virus and characterization of its growth on chorioallantoic membrane of 10- to 12-day-old chick embryos. Pocks produced by smallpox are small and grayish white, whereas those for vaccinia are larger and sometimes hemorrhagic. Variola minor exhibited greater temperature sensitivity on chorioallantoic membranes than did variola major
• real-time PCR
Web resources : Poxvirus Bioinformatic Resource Center
• Mimiviridae
  
• Mimivirus (misnomer : Mimi) is an unclassified dsDNA icosahedral, not filterable and not enveloped virus, with no RNA stage, discovered in 1992, nestling inside an amoeba found inside a cooling tower in Bradford, UK, that was being investigated as the source of an influenza outbreak. Mimivirus defines a new class of nucleocytoplasmic large DNA virus (NCLDV). It measures about 800 nm across, > 4 times as big as a smallpox virus^ref. Mimivirus has a single  circular genome of approximately 1.2 million bases, which is more than many bacteria contain and makes it several times bigger than the largest DNA viruses. > 90% of its DNA does something specific : the bases make up 1,260 genes, which makes it as complex as some bacteria. Mimi carries about 50 genes that do things never seen before in a virus. It can make about 150 of its own proteins, along with chemical chaperones to help the proteins to fold in the right way. It can even repair its own DNA if it gets damaged, unlike normal viruses. And although viruses can use either DNA or RNA to carry their genetic information, Mimi has both. As Mimi carries some genes involved with replication, this could have helped it to spread faster than other viruses. Officially, the virus got its name because it mimics bacteria, but Raoult's father, also a scientist, taught me a story about Mimi the Amoeba when the discoverer was very young, so it's also a tribute to him. Some scientists have speculated that eukaryotes originally evolved from collaboration between a virus and a bacterium. Bacteria could have supplied the ribosomes, the protein factories of the cell, and viruses might have injected their genetic material into a proto-nucleus. One weakness of the theory is that viruses generally lack some of the key genes seen in eukaryotes. But Mimi's complex genome includes these, lending support to the idea^ref. It is a putative human pathogen : serologic evidence of infection was observed in 20% of ICU patients with pneumonia^ref
• Acanthamoeba polyphaga mimivirus
  • Samba virus^ref
• unclassified dsDNA phages
  
• unclassified dsDNA viruses
• Marseillevirus family
• ssDNA viruses
• Anellovirus
• Torque Teno virus (TTV) (a.ka.. TT virus, where TT stands for the initials of the Japanese patient in which it was first isolated by PCR in 1997; nowadays the acronym has been readapted as "transfusion transmitted"). TTV was the first human virus with a single stranded circular DNA genome. TTV was considered to be a member of Circoviridae, but others suggested it conformed to a new family. TTV is distinct from ambisense viruses in the genus Circovirus, since the former genome is negative stranded. The genome structure of TTV is more related to chicken anaemia virus in the genus Gyrovirus, however, the sequence similarity is minimal except for a short stretch at 3816-3851 of TA278.
Genomics : the virus is heterogenous; 16 different genotypes are currently registered, and it can be classified as a "swarm" of at least 5 different viruses.
Epidemiology : depending on the PCR technique used, the prevalence of infection ranges from 1.9 to 36% among blood donors, from 11.5 to 71% in hemodialysis patients, from 47 to 82% among patients with non-A, non-B or non-C fulminant hepatic failure, and the most elevated percentage is found in hemophiliacs. PCR standardization is needed to clearly establish its real prevalence worldwide.
Transmission : epidemiological studies have established that the routes of TTV infection might be parenteral, oral-fecal, and possibly salivary. TTVs are prevalent in non-human primates and human TTV can cross-infect chimpanzees. Furthermore, TTV sequences have been detected in chickens, pigs, cows and sheep. TTV can be transmitted by mother-to-child infection. However, within a year after birth, the prevalence reaches the same level for children born to both TTV-positive and TTV-negative mothers even without breast-feeding.
Pathogenesis : due to the lack of suitable cell systems to support the growth of TTV, the biology of TTV is still obscure. The non-coding region surrounding a short 113 nt GC-rich stretch and occupying approximately one-third of the genome is considered to contain the putative replication origin. 3 mRNAs are expressed by TTV, 3.0 and 1.2 and 1.0 kb species. A protein translated from the 3.0 kb mRNA is considered to be the major capsid protein as well as replicase. The nature of the proteins translated by the other 2 mRNAs are still putative^ref.
=> usually commensal. Its widespread presence in the blood of infected subjects contrasts with the apparent absence of pathological symptoms.
=> non-A, non-G post-transfusional acute hepatitis. TTV may play a role in the pathogenesis of non-A, non-B or non-C fulminant hepatic failure. Patients co-infected with hepatitis C virus (HCV) and TTV have a significantly higher histological grade score than patients with isolated HCV infection
=> might be a contributing factor in liver damage in children^ref and in the lung impairment caused by asthma^ref.
=> in 239 TTV⁺ people, multiple-genogroup infections were common and associated with higher viral loads than would be expected from simple additive effects. The latter observation was restricted to the infections which included both genogroups 1 and 3, pointing to the possible existence of some kind of infection facilitation between these genogroups^ref.
Treatment with IFN seems to decrease TT viremia, according to results obtained outside the context of clinical trials^ref
unclassified Anellovirus
• small anellovirus (SAV) (identified in 2006) is present in the blood of healthy persons (20% prevalence), and also in their PBMNC and saliva samples^{ref1, ref2}
• Small anellovirus 1
• Small anellovirus 2
• Small anellovirus BEC-VIPI
• Small anellovirus DF-VIPI
• Small anellovirus DT-VIPI
• Small anellovirus FIL-VIPI
• Small anellovirus GAR-VIPI
• Small anellovirus GIAN-VIPI
• Small anellovirus KR-BD
• Small anellovirus RIC-VIPI
• Small anellovirus TER-VIPI
• TTV-like mini virus (TTMV) (identified in 2000)^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9}

Epidemiology : 72% of healthy Brazilian blood donors were TLMV DNA positive^ref
Transmission : mother-to-neonatal intrauterine transmission or transmission via breast milk may^ref; adults and children are coinfected frequently with several TLMV isolates of different origins^ref
Pathogenesis : in a few cases, episodes of a considerable increase in viraemia were observed, but in most patients there were no discernible increases as immune deficiency progressed^ref. In patients receiving immunosuppressants subsequent to kidney transplantation, viral titers tended to increase; in soldiers undergoing extreme training known to cause immunosuppression, insignificant increases in titers were observed; and IFN treatment of patients with HCV caused a temporary decrease in TTV and TLMV titers^ref.
• Circoviridae
• unclassified Gyrovirus
• Human gyrovirus type 1 (HGyV)

• Parvoviridae: the parvoviruses: a family of DNA viruses having a nonenveloped virion 18–26 nm in diameter composed of 60 copies of the capsid protein with icosahedral symmetry. The genome consists of a single molecule of linear single-stranded DNA (MW 1.5–2.2 ´ 10⁶, size 4–6 kb). Viruses contain 2–4 major polypeptides, depending on the species, and are resistant to heat, lipid solvents, deoxycholate, and nucleases but sensitive to formalin, b-propiolactone, hydroxylamine, oxidizing agents, and ultraviolet radiation. Replication and assembly occur in the nucleus and require S-phase cellular function in the host cell or the presence of helper virus. Host range is narrow and transmission may be vertical or by mechanical vectors. Canine parvovirus (CPV) is an emerging DNA virus that was first observed to cause disease in canines in 1978 and has since become a ubiquitous pathogen worldwide. CPV emerged from feline panleukopenia parvovirus (FPLV) or a closely related virus, differing at several key amino acid residues. Although FPLV has remained an endemic infection in its host populations, since the 1970s, the newly emerged CPV has undergone an epidemic-like pattern of logistic/exponential growth, effectively doubling its population size every few years. This rapid population growth was associated with a lineage of CPV that acquired a broader host range and greater infectivity. Recombination played no role in the emergence of CPV. Rather, any preexisting variation in the donor species and the subsequent rapid adaptation of the virus to canines were likely dependent on a high rate of mutation and the positive selection of mutations in the major capsid gene. Strikingly, although these single-stranded viruses have a DNA genome and use cellular replication machinery, their rate of nucleotide substitution is closer to that of RNA viruses than to that of double-stranded DNA viruses^ref. There are 2 subclasses:
• Densovirinae, comprising genera that infect invertebrates
• Parvovirinae, comprising 5 genera that infect vertebrates (mammals and birds). Viruses multiply in the nucleus and require S-phase cellular functions for replication. Transmission is transplacental or by mechanical vector. Human parvoviruses cause transient aplastic crisis, acute arthritis, erythema infectiosum, hydrops fetalis, spontaneous abortion, and fetal death. Animal pathogens include bovine, canine, feline, and goose parvoviruses, feline panleukopenia virus, mink enteritis virus, Aleutian mink disease virus, and various murine parvoviruses.
• human parvovirus RA-1 : a species belonging to the genus Parvovirus that has been associated with rheumatoid arthritis
• Amdovirus
• Bocavirus comprise 3 species
• unclassified Bocavirus
• human bocavirus (HBoV) : in 2001, 2 previously unknown parvoviruses were discovered in bovine sera used as diluent. These 2 novel parvoviruses proved to be frequent contaminants of bovine sera^ref. Among the detected viruses were one coronavirus and one parvovirus, both of which were at that time uncharacterized. The parvovirus was in a retrospective clinical study detected in 17 additional patients and associated with lower respiratory tract infections in children^ref. In a 2nd study, Janice Louie of the California Department of Health Services, Lawrence Drew of the University of California, San Francisco and colleagues checked patients reporting to the hospital with flu-like illness including "unspecified upper respiratory infection," acute bronchitis, sinus infections, and pneumonia. They could identify a virus in only 39% of the patients. These included influenza A or B in 54 patients, picornavirus in 28, RSV in 12, human metapneumovirus in four and human coronavirus OC43 in 2 patients^ref. Subsequent to publication of these papers, others have found that HBoV is frequently found in nasopharyngeal samples of hospitalized infants and children with acute respiratory tract diseases. Proving the clinical relevance of HBoV is challenging, because application of some of Koch's revised postulates is not possible. Because of the high rate of coinfections with HBoV and other respiratory tract pathogens, an association between HBoV and respiratory tract diseases remains unproven. For example, a Brisbane study^ref made an additional 206 viral detections, resulting in the identification of a virus in 67.0% of specimens. The majority of the infectious agents were RNA viruses (89.9%). Overall, human rhinoviruses (HRVs) were the most frequently identified target (n = 140) followed by human adenoviruses (HAdVs; n = 25), human metapneumovirus (HMPV; n = 18), human bocavirus (HBoV; n = 15), human respiratory syncytial virus (HRSV; n = 12), human coronaviruses (HCoVs; n = 11), and human herpesvirus-6 (n = 11). HRVs were the sole agent detected in 37.8% (n = 31) of patients with suspected lower respiratory tract infection (LRTI). Genotyping of the HRV VP4/VP2 region resulted in a proposed subdivision of HRV type A into sublineages A1 and A2. Most of the genotyped HAdV strains were found to be type C. This study described the high microbial burden imposed by HRVs, HMPV, HRSV, HCoVs, and the newly identified virus, HBoV on a predominantly pediatric hospital population with suspected acute respiratory tract infections. Of 72 phlegm samples taken from children > 1 year-old in Chenzhou, a city in the central Chinese province of Hunan, 6 have tested positive since October 2005 to August 2006^ref. Human bocavirus has been found in nearly 5% of pneumonia patients in rural Thailand, mostly young children
• Dependovirus : first discovered in 1960s. Particles consist of 50% protein (VP1-3) and 50% DNA (5 Kb, packaging equal amounts of positive and negative strands)
• adeno-associated virus (AAV) 1
• adeno-associated virus (AAV) 2
• adeno-associated virus (AAV) 2H
• adeno-associated virus (AAV) 3
• adeno-associated virus (AAV) 3B
• adeno-associated virus (AAV) 4
• adeno-associated virus (AAV) 5
• adeno-associated virus (AAV) 6
• avian AAV
• canine AAV
• equine AAV
• ovine AAV
Over 40 genomic variants having been reported^ref. It appears that there are several major clades of related variants. Within these clades, many other individual variants appear to have been generated by recombination within the capsid coding sequence between different parental serotypes.
Genomics : 4680 nt

Proteomics :
• the 4 non-structural proteins designated as Rep78, Rep68, Rep52 and Rep40 are the only trans element in the AAV genome which are involved in the regulation of these events : they are necessary for the resolution of the termini during productive replication, accomplished by means of a site-specific, strand-specific nicking activity present in the longer Rep proteins, which are transcribed from the p5 promoter, and differ only at the C-terminus, where spliced and unspliced versions are both translated. These longer Rep proteins are also bifunctional transcriptional regulators, which generally activate AAV gene expression during productive infections and repress it during latency. The shorter Rep proteins are transcribed from the p19 promoter, which is embedded within the long Rep coding sequence. The shorter Reps are necessary for packaging single-stranded AAV genomes into capsids. They also modify the transcriptional regulatory activities of the longer Reps. Rep78/68 interacts with topoisomerase I binding, arginine/serine-rich (TOPORS) to enhance gene transcription. Rep68 interacts with the template-activating factor I/Set oncoprotein (TAF-I/Set) complex^ref. The N terminus of Rep binds the acidic domain of ANP32B, a member of the acidic nuclear protein 32 family which takes part in the formation of the template-activating factor I/Set oncoprotein (TAF-I/Set) complex; through this interaction, Rep was also able to recruit other members of the TAF-I/Set complex, including the ANP32A protein and the histone chaperone TAF-I/Set. Further experiments revealed that silencing of ANP32A and ANP32B inhibited AAV replication, while overexpression of all of the components of the TAF-I/Set complex increased de novo AAV DNA synthesis in permissive cells. Besides being the first indication that the TAF-I/Set complex participates in wild-type AAV replication, these findings have important implications for the generation of recombinant AAV vectors since overexpression of the TAF-I/Set components was found to markedly increase viral vector production^ref
• at the 3' end of AAV genome, the cap gene encodes 3 overlapping structural proteins VP1, VP2 and VP3. These 3 proteins are colinear and identical over their carboxy-terminal portion. VP2 and VP3 represent amino-terminal truncations of VP1. The typical AAV capsid consists of 60 molecules of capsid protein, with a ratio of 3:3:54 of VP1:VP2:VP3 in a nonenveloped icosahedral structure. The crystal structure has recently been published^ref. The structural determinants of AAV2 receptor binding to the heparan sulfate proteoglycan attachment receptor have also been delineated by various mutagenesis studies^ref1,ref2. The differences in binding affinity to different receptors among the various serotypes are likely to be accounted for by differences within these structural determinants, since the key heparin-binding residues are different on nonheparin-binding serotypes^{ref1, ref2}.
• inverted terminal repeats (ITRs) are 145-bp-long palindromic sequences which can assume a T shaped hairpin structure. This special configuration serves as the origin for viral DNA replication. In addition, the ITRs are essential for successful virus packaging, replication, integration and rescue of the vector genome. Recent studies also indicate that the ITR possess some transcriptional promoter activity, albeit relatively weak^ref. The Rep78 and Rep68 can both bind to the ITR at GAGY tandem repeats and nick duplex ITR in a site- and strand-specific manner. This cleavage reaction within the ITR allows the continuous replication of the AAV genome.
• D sequence is the only non-palindromic sequence in the ITR. Its 20-nucleotides contain :
• terminal resolution site (TRS)
• AAV packaging signal
A single ITR with 2 D sequences permits the replication and packaging of the AAV gernome. However, in the absence of the D sequence, the hairpin stuctures are insufficient for the encapsidation of the AAV genome. Although exact nucleotide sequences are not conserved among the identified AAV ITRs from various AAV serotypes, the overall T shaped hairpin structure is maintained. Generally, the Rep proteins from one AAV serotype can complement the ITRs from another AAV serotype. The only exception is AAV5, which has the least homology with any of the known AAV serotypes and its ITR has a unique TRS site.
Receptors :
• AAV1 uses ?
• AAV2 (the most commonly used serotype) uses^refheparan sulfate proteoglycan (HSPG)^ref (poorly expressed on the apical surface of polarized ciliated respiratory epithelial cells), and the FGFR-1 (ubiquitous) and a_vb₅ integrin as coreceptor^ref
• AAV3 uses heparan sulfate proteoglycan (HSPG)
• AAV4 uses O-linked sialic acid^ref
• AAV5 uses N-linked sialic acid^ref and PDGFRab (lung, central nervous system, muscle and eye)^ref
AAV vectors transduce cells by multiple pathways, including integration at nonhomologous chromosomal locations by an unknown mechanism.
• in absence of cell-stressing agents (helper functions), they integrate in a site specific manner (in the case of AAV2, ~ 70% of integration occurs in 19q13.3-qter, the adeno-associated virus integration site 1 (AAVS1)) through rep-mediated semihomologous recombination (only 30 bp homology) and establish long-term latency within mammalian cells. Existing spontaneous chromosome breaks facilitates vector integration, which has implications for their clinical use, as demonstrated in cells containing a specific chromosomal double-strand break created by the endonuclease I-SceI or multiple breaks created by treatment with etoposide or g-irradiation^ref
• in the other case they undergo lytic life cycle
=> asymptomatic infection is common in humans (at age 20, 85% has neutralizing Abs : 5-10% has vDNA in muscle cells !) and in many animal species
Used as transfection vector.
• Erythrovirus
• B19 virus / human parvovirus B19
  
Genomics : discovered in 1974; the 5.6-kb genome codes for only 3 major proteins, the 2 overlapping capsid proteins VP1 and VP2 and the non-structural protein NS1. Surprisingly high rate of evolutionary change, at approximately 10(-4) nucleotide substitutions per site per year. This rate is more typical of RNA viruses and suggests that high mutation rates are characteristic of the Parvoviridae^ref.
Receptor : erythrocyte P blood group antigen
Susceptibility : HLA-DRB1*01, DRB1*04 , and DRB1*07 alleles
Transmission : respiratory route.
Pathogenesis : B19 targets immature erythroid cells in the bone marrow. Autoantibodies produced in the wake of B19 infection include ANAs, anti-DNA, anti-SSA/SSB, and anti-phospholipids. Clinical resolution of acute infection is associated with the emergence of antiviral IgG, which is maintained lifelong^ref. However, although antibodies are of importance, evidence for an important role for cellular immune responses in the control of B19 infection is also emerging. In some individuals with apparently intact antibody responses, virus replication continues long term^ref. Readily detectable CD8⁺ T cell responses in three asymptomatic seropositive individuals have also been observed^ref. CD8⁺ T cells play an essential role in the control of viral infections by direct killing of virus-infected cells and through cytokine secretion. After a primary viral infection, naïve antigen-specific T cells expand clonally and undergo several differentiation stages, followed by a contraction phase mediated by apoptosis. Expression of the chemokine receptor CCR7 on memory T cells has been used to divide this population into central and effector memory subsets. CCR7⁺ “central” memory lymphocytes mostly home to secondary lymphoid organs and have a high proliferative capacity in response to antigen re-encounter. CCR7^- “effector” memory cells home to non-lymphoid organs and are capable of rapid effector function^ref. Peptide–MHC multimers can be used to further quantify and phenotype T cells bearing T cell receptors of appropriate peptide/HLA specificity^{ref1, ref2}. Amongst “effector” memory populations, a spectrum of phenotypes exists, as assessed by surface expression of markers such as CD27, CD28, and CD57, and intracellular expression of perforin. Amongst the viral infections studied, cytomegalovirus (CMV) is associated with the emergence of the largest long-term memory populations with the most “mature” phenotype, CD27/CD28 ^low, CD57 ^high, and often perforin positive^ref. The factors that ultimately determine the phenotype and function of these populations of lymphocytes are not fully understood, but continued exposure to antigen is thought to be important. Persistent infections such as HCV, EBV, and HIV also show antiviral populations that are “effector” (CD62L^low or CCR7^low), but show lower levels of maturation than CMV-specific responses^ref. B19-specific CD8⁺ T cell responses during and after acute adult infection was studied using HLA–peptide multimeric complexes. Surprisingly, these responses increased in magnitude over the first year post-infection despite resolution of clinical symptoms and control of viraemia, with T cell populations specific for individual epitopes comprising up to 4% of CD8⁺ T cells. B₁₉-specific T cells developed and maintained an activated CD38⁺ phenotype, with strong expression of perforin and CD57 and downregulation of CD28 and CD27. These cells possessed strong effector function and intact proliferative capacity. Individuals tested many years after infection exhibited lower frequencies of B₁₉-specific cytotoxic T lymphocytes, typically 0.05%–0.5% of CD8⁺ T cells, which were perforin, CD38, and CCR7 ^lowref
=> asymptomatic
=> papular-purpuric gloves-and-socks syndrome
=> erythema infectiosum / epidemic megaloerythema / "fifth" disease of the infant / "slapped cheek" syndrome after 5-15 days incubation :
• symmetric, bilateral, butterfly morbilliform maculopapular exanthema on face => arms and hips => trunk; followed by ...
• acute polyarthritis of hands, knees, whistles and ankles (5-10% of babies and 50-60% of adults, sometimes without feveror exanthema) self-limiting with 2-21 days. Acute B₁₉ infection can simulate early RA or SLE (butterfly rash over the cheeks, cytopenia, etc.)^{ref1, ref2}. In addition, there have been a few reports of erosive RA or SLE developing shortly after a B₁₉ infection, with positive PCR tests for B₁₉ DNA in synovial tissue or blood cells. Studies in large series indicate that B₁₉ is probably an extremely rare cause of RA or SLE. Vasculitides affecting the small vessels (Henoch-Schonlein purpura, Wegener's granulomatosis), medium-sized vessels (periarteritis nodosa), and large vessels (giant cell arteritis) can occur after B₁₉ infection
• in patients with hemolytic anemia or sickle cell disease it causes aplastic anemia for 7-10 days (it undergoes chronicization in immunocompromised individual); persistent infection in immunocompromised patients can lead to chronic bone marrow failure
• peripheral neuropathies
• meningitis
• encephalopathies
• myocarditis : myocardial endothelial cells, not cardiac myocytes, have been identified as parvovirus B19–specific target cells^ref. The high prevalence of parvovirus B19 genomes in 35% of patients with chronic dilated cardiomyopathy strongly suggests that chronic cardiac disease develops from previous parvovirus B19–associated myocarditis^ref.
• if a mother becomes affected in the second trimester of pregnancy => fetal hydrops, fetal death, and spontaneous abortion and acute hepatitis (liver is the fetal hematopoietic organ).
Laboratory examinations :
• giant basophilic proerythroblasts, erythroblasts with dog-eared cytoplasmic projections, vacuolated proerythroblasts, hemophagocytic syndrome like-cells, no Pelger anomaly
• identification of PVB19 by means of routine histology and immunohistology is only given in lytic infections occurring in transient aplastic anemia or nonimmune hydrops fetalis by the detection of viral inclusion bodies in erythroid precursor cells
• in all other PVB19-associated diseases, PCRmethods must be applied.
• in situ hybridization demonstrated that endothelial cells of the microcirculatory periphery of the heart and hepatobiliar system in lytic infections are PVB19-specific target cells in children and adults.
• specific IgG avidity index (AI)^ref
• unclassified Erythrovirus
• Human erythrovirus V9
• Human erythrovirus VX
• Parvovirus
• unclassified Parvovirus
• Human parvovirus 4
• unclassified Parvovirinae
• Bufavirus (3 genotypes) : in feces from children with acute diarrhea in Burkina Faso (4%)^ref, 1.1% of children and adults in Finland^ref, and Bhutan (0.8%)^ref but not Chile^ref, children with acute flaccid paralysis in Tunisia^ref (1.6%) and 1 case of idiopathic diarrhea in the Netherlands^ref. The identified BuV DNA in our samples could originate from previous or current infections unrelated to gastroenteritis, or be associated with prolonged virus secretion in the respiratory or digestive tracts, a phenomenon shown, e.g., for bocavirus^{ref1, ref2}. Acquisition of the virus from a food source cannot be ruled out, although 1 patient harbored the DNA for at least 4 days, during which a 10-fold increase in viral load was observed.
• Human parvovirus 5
• dsRNA viruses : RNA templates and RNA-directed RNA polymerase (RdRP) are packaged together in a core or shell of viral proteins within which RNA synthesis occurs.
• Reoviridae : the reoviruses: a family of RNA viruses having a nonenveloped icosahedral virion 60–80 nm in diameter; virions have two protein shells, the particle with the outer shell removed being referred to as the core. The genome consists of 10 to 12 structural segments of linear double-stranded RNA (total MW 12–20 x 10⁶, 10–27 kbp depending on the genus). Virions contain 10–12 structural proteins, including a transcriptase, and are resistant to heat but sensitive to lipid solvents. Replication and assembly occur in the cytoplasm.
Transmission is by the fecal-oral route, by fomites, or by arthropod vectors.
Proteomics : fusion-associated small transmembrane (FAST) proteins of the fusogenic reoviruses are the only known examples of membrane fusion proteins encoded by nonenveloped viruses.
Some genera contain arthropod and plant pathogens. Vertebrate pathogens are included in the genera :
• Aquareovirus infect fresh- and salt-water fish and invertebrates; some species cause economically important diseases of fish.
• Coltivirus : tickborne vertebrate viruses having 12-segmented dsRNA genomes
Genomics : Coltivirus particles are 80 nm in diameter and have a core 50 nm in diameter. Electron microscopic studies^{ref1, ref2} have shown particles with a relatively smooth surface capsomeric structure and icosahedral symmetry. Most viral particles are nonenveloped, but a few acquire an envelope structure during passage through the endoplasmic reticulum^{ref1, ref2}. The buoyant density of CTFV in CsCl is 1.36–1.38 g/cm³. The virus is stable between pH 7.0 and 8.0 but loses infectivity at pH 3.0. CTFV can be stored at 4°C for 2–3 months in 50% fetal calf serum, 0.2 mmol/L Tris-HC1, pH 7.8, or for years at –80°C. Upon heating to 55°C, CTFV loses its infectivity. The virus is stable when treated with nonionic detergents (such as Tween 20) or with organic solvents (such as Freon 113 or its ozone-friendly substitute Vertrel XF), but viral infectivity is abolished by treatment with sodium deoxycholate or sodium dodecyl sulfate^ref (Attoui H, Mohd Jaafar F, de Lamballerie X, Mertens PPC. Coltivirus, Reoviridae. In: Fauquet CM, Mayo MA, Maniloff J, Desselberger U, Ball LA, editors. Virus taxonomy: eighth report of the international committee on taxonomy of viruses. London: Elsevier/Academic Press; 2005. p. 497–503). The genome consists of 12 dsRNA segments designated Seg-1 to Seg-12 in order of reduced molecular weight as observed during agarose and polyacrylamide gel electrophoresis. The genome contains 29,000 bp and segment size ranges from 675 bp to 4,350 bp^{ref1, ref2}. The genomic dsRNA of CTFV has an electropherotype similar to that of CTFV-Ca. CTFV produces a cytopathic effect (CPE) in mammalian cells, including human carcinoma cells, monkey kidney cells (buffalo green monkey [BGM] and Vero), hamster kidney cells (BHK-21), and mouse fibroblasts (L-929). Cells infected with CTFV develop granular matrices that contain viruslike particles in the cytoplasm. These structures are similar to viral inclusion bodies produced during orbivirus infections^ref. In addition, bundles of filaments (tubules) characterized by cross-striations and kinky threads are found in the cytoplasm and, in some cases, in the nucleus of infected cells^{ref1, ref2} (Attoui H, Mohd Jaafar F, de Lamballerie X, Mertens PPC. Coltivirus, Reoviridae. In: Fauquet CM, Mayo MA, Maniloff J, Desselberger U, Ball LA, editors. Virus taxonomy: eighth report of the international committee on taxonomy of viruses. London: Elsevier/Academic Press; 2005. p. 497–503). These tubules may also be comparable to those found in orbivirus-infected cells. > 90% of virus particles remain associated with debris after cell disruption. Sequence analysis of coltivirus genomes has shown that segment 6 of viral protein 6 (VP6) of CTFV is homologous to segment 7 (VP7) of EYAV. The amino acid sequence (residues 370–490) of VP7 of EYAV showed 50% similarity to the sarcolemmal-associated protein of the European rabbit O. cunniculus, which may be the major host of EYAV. By comparison, VP6 of CTFV showed no similarity with this rabbit protein^ref, which may be the result of insertion of a sequence encoding a lagomorph protein into segment 7 of EYAV. Reading through a stop codon, which is common in retroviruses and alphaviruses, was reported in coltiviruses, particularly in segment 9, where long and short proteins are produced from a single open reading frame^ref. Antigenic variation between CTFV strains is low, especially between strains from humans^ref. Distinct CTFV serotypes are difficult to define^ref, and immunity to reinfection has been observed^ref. CTFV from North America and EYAV from Europe show little cross-reactivity in neutralization assays. CTFV-Ca cross-reacted with CTFV, but not with EYAV, and may be a serotype of CTFV. Two species of coltiviruses have been identified: CTFV, with 2 serotypes represented by CTFV-F1 and CTFV-Ca, and EYAV. Overall identities between nucleotide sequences from segments 9, 10, 11, and 12 of CTFV strains range from 90% to 100%: 97–100% for segment 9, 96–99% for segment 10, 90–94% for segment 11, and 94–96% for segment 12. The degree of identity between nucleotide sequences of segments 1–12 of CTFV and EYAV isolates ranges from 55 to 88%^ref. The genome of CTFV contains 29,174 nucleotides, and that of EYAV contains 29,210 nucleotides^ref. All 12 segments of CTFV and EYAV have conserved sequences that are located at their termini. The motifs 5´-G/CACAUUUG-3´ and 5´-UGCAGUG/C-3´ are found in the 5´ and 3´ noncoding regions of CTFV, respectively, and the motifs 5´-GACAA/UUU-3´ and 5´-UGC/UAGUC-3´ are found in these noncoding regions in EYAV. The 5´ and 3´ terminal trinucleotides of all segments in both viruses are inverted complements^ref. Genome characterization has helped shed light on the origin of EYAV. Genetic findings support the hypothesis that EYAV was derived from a CTFV-like ancestor virus that was introduced into Europe through Asia when lagomorph ancestors migrated from North America 5–50 million years ago^ref. The antigenic and genetic relationships between CTFV and EYAV are further corroborated by their identical morphologic features, as analyzed by electron microscopy^ref.
• Colorado tick fever virus (CTFV) was isolated by Florio and others (Florio L, Stewart M, Mugrage ER. The etiology of Colorado tick fever. J Exp Med. 1946;83:1–10) in 1946 from human serum by injection into adult hamsters. The virus was adapted to egg and mice, and suckling mice became the routine isolation system for CTFV^{ref1, ref2} (Florio L, Stewart M, Mugrage ER. The etiology of Colorado tick fever. J Exp Med. 1946;83:1–10)

California hare coltivirus (CTFV-Ca), identified as strain S6-14-03, was isolated from the blood of the white hare, L. californicus, black-tailed jackrabbit), in northern California (outside the range of D. andersoni)^ref

Salmon River virus (SRV), which may be a serotype of both CTFV and CTFV-Ca, isolated from a person with moderately severe CTF-like illness in Idaho

Epidemiology : regions of the Rocky Mountains area and Pacific slope of the USA and Canada, where it causes CTF, a human disease initially confused with a mild form of Rocky Mountain spotted fever, which is caused by Rickettsia rickettsii. Antibodies to CTFV antigen have been detected in sera of humans in South Korea (C. Calisher, pers. comm.).
Transmission : a zooanthroponosis; vector : wood tick Dermacentor andersoni, but other ticks such as Dermacentor occidentalis, Dermacentor albopictus, Dermacentor arumapertus, Haemaphysalis leporispalustris, Otobius lagophilus, Ixodes sculptus, and Ixodes spinipalpisare also infected with the virus. CTFV is transmitted transstadially, but not transovarially. Infected larvae and nymphs can hibernate, and the nymphal and adult ticks become persistently infected. In certain rodents viremia can persist for >5 months. These ticks and rodents may provide hosts by which the virus could overwinter. The prevalence of viremia in rodents in a virus-endemic area ranges from 3.5% to 25%, and the prevalence in ticks ranges from 10% to 25%^ref. CTFV has a wide host range that includes ground squirrels, chipmunks, wild mice, wood rats, wild rabbits and hares, porcupines, marmots, deer, elk, sheep, and coyotes. Person-to-person transmission of CTFV can occur by blood transfusions (Philip RN, Casper EA, Cory J, Whitlock J. The potential for transmission of arboviruses by blood transfusion with particular reference to Colorado tick fever. In: Greenwalt J, Jamieson GA, editors. Transmissible disease and blood transfusions. New York: Grune and Stratton; 1975. p.175–96). This virus is included on the list of agents screened before bone marrow transplantation in the USA^ref. Prolonged viremia observed in humans and rodents is due to the intraerythrocytic location of virions, which protects them from immune clearance^{ref1, ref2, ref3}.
=> Colorado tick fever / mountain tick fever : 4-6 days incubation => high (biphasic) fever, leukopenia, arthromyalgia, nausea and vomiting, petechiae on limbs and maculopapular exanthema on trunk
Prevention : patients infected with CTFV show long-lasting immunity. An experimental vaccine was developed in the 1960s and produced long-lasting immunity, but production was stopped in the 1970s.

Eyach virus (EYAV) was isolated in Europe in 1976 from Ixodes ricinus ticks (EYAV-Gr) and in 1981 from Ixodes ricinus (EYAV-Fr578) and Ixodes ventalloi(EYAV-Fr577)^ref. Its antigenic relationship to CTFV was established by a complement-fixation assay^ref. Genome sequence analysis showed that CTFV and EYAV are closely related^refand confirmed the antigenic observations. Serologic surveys in France identified antibodies to EYAV in 1.35% of animals, including the European rabbit (Oryctolagus cunniculus), mice, mountain goats, domestic goats, sheep, and deer^ref. The presence of EYAV was suspected in Europe because anti-EYAV antibodies were detected in patients with neurologic disorders. However, the natural cycle of the virus is still unclear, and whether it circulates continuously in Europe is not known, although the rabbit O. cunniculus is suspected of being main host^{ref1, ref2}. In 2003, the virus was reisolated from I. ricinus ticks in Germany^ref
=> abrupt onset of fever, chills, headache, retroorbital pain, photophobia, myalgia, abdominal pain, and generalized malaise. Diphasic or triphasic febrile patterns have been observed, usually lasting for 5 to 10 days. Severe forms of the disease that involve infection of the central nervous system (CNS) or hemorrhagic fever, pericarditis, myocarditis, and orchitis have been rarely observed, mainly in children. Severity is sufficient to result in hospitalization of 20% of patients. Offspring of mice experimentally infected with CTFV showed teratogenic effects^ref. Mother-to-infant transmission has been reported in pregnant women. The incidence of complications in different reports of infection with CTFV has been reported as <7%^{ref1, ref2, ref3, ref4}. CTFV causes leukopenia (65% of infected humans), with mean leukocyte counts of 900/mL to 3,900/mL, and thrombocytopenia, with platelet counts of 20,000/mL to 95,000/mL^ref. Patients with neurologic disorders (meningitis, meningoencephalitis, encephalitis) show lymphocyte infiltration of cerebrospinal fluid (CSF), and the virus has been isolated from CSF. CTFV infections have been confused with other tickborne diseases such as Rocky Mountain spotted fever (a rickettsial disease), tularemia, relapsing fever, and Lyme disease. However, rash and leukocytosis distinguish Rocky Mountain spotted fever from CTF. Signs in the CNS confuse CTF with other causes of viral meningitis and encephalitis, including St. Louis encephalitis virus, Western equine encephalitis virus, and enteroviruses.CTFV can be isolated from blood because it is present in circulating erythrocytes for as long as 4 months^ref, and it infects the hematopoietic progenitor cells and remains sheltered in erythrocytes after maturation. Intracerebral injection of blood into suckling mice is considered the most sensitive isolation system. Reverse transcription–polymerase chain reaction (RT-PCR) was developed for diagnosis of CTFV infection, and this method detected human and tick virus isolates >3 days postinfection in experimentally infected mice^ref. As little as 1 genome could be detected by using a PCR assay^ref. Serologic diagnostic methods based on CTFV-infected cell cultures have also been developed^ref. These include 1) a complement-fixation test that is relatively insensitive because in 25% of patients complement-fixing antibodies are not detected and in 75% of patients these antibodies appear late after infection; 2) a seroneutralization assay for detection neutralizing antibodies that appear 14–21 days after onset of disease; 3) an immunofluorescence assay that uses CTFV-infected BHK-21 or Vero cells and is an easy and rapid test for detecting anti-CTFV antibodies; and 4) an enzyme-linked immunosorbent assay (ELISA) for immunoglobulin M (IgM) and IgG that appear concurrently or a few days after neutralizing antibodies (peak 30–40 days after infection), However, IgM titers decrease sharply after day 45. An ELISA based on recombinant VP7 and a Western blot based on synthetic VP12 showed good sensitivity in detecting antibodies to CTFV^{ref1, ref2}. A complement fixation assay has been developed for detection of EYAV^ref. It detected anti-EYAV antibodies in 158 Czechoslovakian patients with encephalitis in whom tickborne encephalitis had been diagnosed. This population was also tested for tickborne encephalitis viruses (Kemerovo, Lipovnik, or Tribec) and antibodies to EYAV. Seventeen serum specimens (11%) had only anti-EYAV antibodies. The same test identified anti-EYAV antibodies in 8 (17%) of 47 patients with polyradiculoneuritis and meningopolyneuritis^ref. Recently, an ELISA based on recombinant VP6 of EYAV was developed. This test selectively identified anti-EYAV antibodies^ref. An RT-PCR assay based on the sequence of genome segment 12 has also been developed for specific detection of EYAV^ref
• Orbivirus, separable into at least 14 antigenically distinct groups, and infecting a variety of vertebrates, including humans. It includes the agents of bluetongue and African horse sickness. Mosquitoes, sandflies, and ticks are vectors.
• Kemerovo virus group
• Great Island complex
• Broadhaven virus
• Kemerovo virus : a tickborne virus that causes a benign febrile disease in western Siberia and Egypt
• Lipovnik virus
• Tribec virus
• Orungo virus group
• Orungo virus
=> febrile illness in Nigeria and Uganda
• Orthoreovirus infect a wide range of animals and are distributed worldwide. No causative relationship to any disease has been proved in humans, although reoviruses have been isolated from both healthy individuals and patients with a variety of diseases. In other mammals reoviruses are associated with respiratory and enteric disease, and in chickens and turkeys, with arthritis. Experimentally in mice, orthoreoviruses may cause a wide spectrum of disease, and viruses isolated from primates have been associated with neurological disease. Avian orthoreoviruses can cause severe disease outbreaks in domestic flocks but do not infect mammals
• Mammalian orthoreoviruses
• Mammalian orthoreovirus serotype 1
• Mammalian orthoreovirus serotype 2
• Mammalian orthoreovirus serotype 3
=> murine lymphoma^{ref1, ref2, ref3, ref4, ref5, ref6,ref7}, rabbit lymphoma^ref, human Hodgkin's lymphoma^ref and Burkitt's lymphoma^{ref1, ref2, ref3, ref4, ref5, ref6, ref7}
=> neonatal infection causes biliary ways atresia; murine chronic hepatitis^ref
Proteomics : reoviruses deal the host cell a double blow by activating apoptotic pathways and inhibiting DNA damage repair genes. Both mechanisms ultimately lead to cell death.
• viral attachment protein sigma1 (an elongated fiber comprised of an N-terminal tail that inserts into the virion and a C-terminal head that extends from the virion surface) binds to F11 receptor (F11R) / junction adhesion molecule A (JAM-A)^ref and induces apoptosis (mitochondrial release of Smac/DIABLO, down-regulation of survivin, XIAP, and IAP1)^ref. JAM-1 was the first of a family of related proteins (JAM family) to be discovered. Two proteins with structural and sequence similarities to JAM-1, named JAM-2 and JAM-3, have been identified more recently. JAM-1 is specifically localized at the tight junctions of epithelial and endothelial cells and is involved in the regulation of junctional integrity and permeability. This function is attributed to its ability to interact in a homophilic manner. JAM-1 can also bind in a heterophilic manner as it serves as a ligand for integrin LFA-1 (CD11a/CD18), and plays a key role in the process of leukocyte transmigration. In addition, JAM-1 is also a receptor for reovirus, and is a platelet receptor involved in platelet adhesion and antibody-induced platelet aggregation^ref.
Transmission : enteric or respiratory route.
=> subclinical infections
=> mild gastroenteritis in newborns and babies
=> URT infection in newborns and babies
=> mild URT infection (acuterhinitis or pharyngotonsillitis)
• Rotavirus have a wheellike appearance : 11 structural segments of linear double-stranded RNA
• Group B rotaviruses
• Human rotavirus B
• Group C rotaviruses
• Human rotavirus C
• Human rotavirus
• Human rotavirus (serotype P13 / strain 1845)
• Human rotavirus 1
• Human rotavirus 2
• Human rotavirus 3
• Human rotavirus 4
• Human rotavirus 9
• Human rotavirus A (VP6 Ag)
• Human rotavirus G (pararotaviruses or atypical rotaviruses)
• Human rotavirus (serotype G / strain B37)
• Human rotavirus (serotype G / strain RK9)
• human rotavirus DG8
• Human rotavirus serotype G1
• Human rotavirus serotype G2
• Human rotavirus serotype G3
• Human rotavirus serotype G4
• Human rotavirus serotype G6
• Human rotavirus serotype G8
Epidemiology : first reported in 1973; worldwide every year 111 million children under age 5 become mildly ill, 25 million sick enough to require a clinic visit, 2 million require hospitalization, and 440,000-600,000 die (82%  in the poorest countries)^ref; it is the most common cause of severe diarrhea in children in the USA. Virtually all children have one or more rotavirus infections in the first 5 years of life. Each year in the USA, rotavirus is responsible for approximately 500,000 physician visits, 70,000 to 120,000 hospitalizations and 200 infant deaths. It is a seasonal disease in the USA with the vast majority of the disease occurring in the winter and spring months. Outbreaks affecting the elderly in institutionalized settings are not uncommon.
• since 29 Jan to 24 Feb 2004, 28 255 people (of whom 17 032 are under 5 years of age; 15-60% laboratory confirmed) and 50 children have died in Guatemala. During the first 3 weeks of the outbreak, the increase in relation to 2003 was 9%, falling to 4% in the 4th week. The outbreak has affected above all the health districts of Ixcan, Peten Sur Oriente, and Escuintla, but has also spread to Guatemala, Sacatepequez, Suchitepequez, Quetzaltenango, San Marcos, El Progreso, and Zacapa.
• since Jan 2004, 1350 cases and 2 deaths in the resort town of Montego Bay, Jamaica. During 2003, > 28 000 cases (14 deaths) of gastroenteritis were reported in this Caribbean country of 2.6 million residents, up from about 20 000 (5 deaths) in 2002
• since February 2004, 108 confirmed cases have been reported of rotavirus-associated diarrhea in El Salvador, of which 86 percent have occurred in children under 2 years of age. The Departments most affected have been Santa Ana (with 58.3% of the cases) and San Salvador (with 20.4%). To date, no deaths have been reported.
Proteomics :
• NSP3 / NS34 is functional homolog of the cellular poly(A) binding protein (PABP) that interacts with ubiquitous tetratricopeptide containing protein RoXaN and binds to viral mRNA 3' consensus sequences and circularizes mRNA via interactions with eIF4G1
• NSP4 enterotoxin. Diarrhoea may be caused by several mechanisms including :
• malabsorption that occurs secondary to the destruction of enterocytes of the duodenum and upper ileum
• villus ischaemia and activation of the enteric nervous system (ENS) that may be evoked by release of a vasoactive agent from infected epithelial cells in the absence of significant pathologic lesions or enterocyte damage and may be cyclic nucleotide dependent
• intestinal secretion stimulated by the intracellular or extracellular action of NSP4 => [Ca²⁺]_i elevation => age-dependent halide ion movement across the plasma membrane, transepithelial Cl^-secretion, and, unlike many microbial enterotoxins, initial cyclic nucleotide independence to secretory diarrhea. NSP4-mediated [Ca²⁺]_i mobilization may further facilitate diarrhea by signaling through other Ca²⁺-sensitive cellular processes (cation channels, ion and solute transporters) to potentiate fluid secretion while curtailing fluid absorption
Both phases of diarrhea occur in the absence of significant inflammation
• trypsin cleavage of VP4 primes the virus for entry by triggering a rearrangement that rigidifies the VP4 spikes into  a coiled-coil stabilized trimer. VP4 also undergoes a second rearrangement, in which the oligomer reorganizes and each subunit folds back on itself, translocating a potential membrane-interaction peptide from one end of the spike to the other. This rearrangement resembles the conformational transitions of membrane fusion proteins of enveloped viruses^ref.
• viroplasms are discrete structures formed in the cytoplasm of rotavirus-infected cells and constitute the replication machinery of the virus. The non-structural proteins NSP2 and NSP5 localize in viroplasms together with other viral proteins, including the polymerase VP1, VP3 and the main inner-core protein, VP2. NSP2 and NSP5 interact with each other, activating NSP5 hyperphosphorylation and the formation of viroplasm-like structures (VLSs)^ref. Phosphorylation of Ser⁶⁷ within the SDSAS motif (amino acids 63-67) by casein kinase 1a is required to trigger hyperphosphorylation of NSP5 (4 serines (Ser¹⁵³, Ser¹⁵⁵, Ser¹⁶³, and Ser¹⁶⁵) within an acidic region with homology to casein kinase II (CKII) phosphorylation sites^ref) by promoting its activator function^ref. Expression of anti-NSP5 intrabodies in rotavirus-infected cells largely reduces the assembly of viroplasms and CPE. Replication of dsRNA is partially inhibited, despite there being no reduction in virus titre, demonstrating for the first time a key role for NSP5 during the virus replicative cycle^ref. Genome segment 11 encodes the non-structural protein NSP5 and, in some strains, also NSP6. NSP5 is produced soon after viral infection and localizes in cytoplasmic viroplasms, where virus replication takes place. RNA interference by small interfering (si) RNAs targeted to genome segment 11 mRNA of 2 different strains blocked production of NSP5 in a strain-specific manner, with a strong effect on the overall replicative cycle : inhibition of viroplasm formation, decreased production of other structural and non-structural proteins, synthesis of viral genomic dsRNA and production of infectious particles^ref. Fusion of tags induces spurious phosphorylation of rotavirus NSP5^ref. A strong interaction of VP1 with NSP5 but only a weak one with NSP2 was found in co-transfected cells in the absence of other viral proteins or viral RNA. By contrast, VP2 could not be co-immunoprecipitated with anti-NSP5 antibodies or NSP5 with anti-VP2 antibodies. A tagged form of VP1 co-localizes in viroplasms and in VLS formed by NSP5 and NSP2. The tagged VP1 was able to replace VP1 structurally by being incorporated into progeny viral particles. When applying anti-tag-VP1 or anti-NSP5 antibodies, co-immunoprecipitation of tagged VP1 with NSP5 was found. Using deletion mutants of NSP5 or different fragments of NSP5 fused to EGFP, the 48 C-terminal amino acids were identified as the region essential for interaction with VP1^ref
• VP7 outer capsid protein of rotavirus induces polyclonal B-cell activation^ref and has homology to transglutaminase 2 / tissue transglutaminase (tTG), C polypeptide, so molecular mimicry could cause celiac disease^ref
The 2 glycoproteins, one structural (VP7) and one non-structural (NSP4), mature and remain in the ER thanks to 3 amino acids in the N terminus and a region between amino acids 85 and 123 in the cytoplasmic region of NSP4, respectively^ref
Transmission : fecal contamination of food and water (stable in the environment and can remain viable for long periods of time. This permits transmission from contact with contaminated surfaces, water, or food)
=> acute gastroenteritis after 1-4 days incubation : nausea and vomiting, diarrhea, abdominal pain, and fever. Dehydration (sunken eyes) is common and if not dealt with promptly has serious consequences. Severe diarrhea and dehydration occur primarily among children 3 months to 35 months of age. In 2 patients with rotavirus gastroenteritis who developed encephalopathy, rotavirus RNA was detected in the cerebrospinal fluid (CSF) by RT-PCR; in 1 patient, rotavirus RNA was detected on 2 occasions 3 weeks apart. There are increasing reports of cases in which patients who have seizures after an episode of rotavirus diarrhea have evidence of rotavirus in their CSF. A search of 2 large hospital discharge databases suggested that seizures are noted as part of the discharge diagnosis in the records of, at most, <4% of patients with rotavirus diarrhea versus 7% of patients with bacterial diarrhea. Although evidence suggesting that rotavirus is a cause of central nervous system sequelae remains inconclusive, the 2 case reports presented in this study further illustrate a possible association. Further study is required to determine whether detection of rotavirus in CSF represents a true pathogen, CSF contamination that occurs at the time of lumbar puncture or in the laboratory, or carriage of rotavirus RNA in trafficking lymphocytes^ref : a case of rotavirus cerebellitis was reported^ref
Laboratory examinations : > 3 watery or looser-than-normal stools within a 24-hour period or forceful vomiting, along with the detection of rotavirus by enzyme immunoassay in a stool specimen obtained within 14 days after the onset of symptoms. G serotypes were identified by one-step RT-PCR analysis followed by sequencing^ref. All rotavirus-positive stools were to be evaluated for vaccine strains by viral culture with the use of a plaque assay and RNA electropherotyping. Electron microscopy shows abundance of virus particles in the feces; ethyl dodecanoate (which smells of pears) in diarrhea
Therapy : approximately 1 out of every 40 children with gastroenteritis caused by rotavirus will require hospitalization and therapy providing fluids intravenously. Compliance with the oral-rehydration standards set by the global WHO strategy for Integrated Management of Childhood Illness (IMCI) is extremely important in these cases.
Prevention : there are no approved attenuated vaccines for rotavirus. Efforts to develop an effective and safe vaccine resulted in licensing in 1998 of a live oral vaccine (RotaShield) that was withdrawn less than one year later, after 9 reports of intussusception occurred within the 1st 7 months of vaccine use, more than double the cases reported in the previous 7 years. Intussusception occurs when the intestine telescopes into itself, causing an obstruction of the bowel that may have to be repaired surgically. An investigation of vaccinated infants confirmed that the vaccine was indeed the cause of the complication. Most of these infants had intussusception shortly after their vaccination. The risk of intussusception was 10 times higher than normal, and within the 1st 7 days after vaccination, the risk was 14 times higher than normal. This experience with RotaShield has resulted in the development of new candidate rotavirus vaccines that are currently in late phase III clinical trials. One of these vaccines, GlaxoSmithKline's Rotarix, was licensed in July 2004 to be used in Mexico^ref.
Web resources : International Rotavirus Symposium
• Seadornavirus (Southeast Asian dodeca RNA virus^ref : Attoui H, Mohd Jaafar F, de Lamballerie X, Mertens PPC. Seadornavirus, Reoviridae. In: Fauquet CM, Mayo MA, Maniloff J, Desselberger U, Ball LA, editors. Virus taxonomy: eighth report of the international committee on taxonomy of viruses. London: Elsevier/Academic Press; 2005. p. 504–10):
Epidemiology : these viruses are endemic in Southeast Asia, particularly Indonesia and China. BAV was first isolated in 1987 from CSF (2 isolates) and sera (25 isolates) of patients with encephalitis in southern China (Yunnan Province). Numerous isolates were also obtained from other patients with encephalitis^{ref1, ref2} (33,34). A virus described as an isolate of BAV was identified in western China (Xinjiang Province) from patients with fever and flulike manifestations (Li QP. First isolation of 8 strains of new orbivirus (Banna) from patients with innominate fever in Xinjiang. Endemic Dis Bull. 1992;7:77–82). Virus isolates from pigs and cattle with genomes having the same electropherotype as BAV were also reported^ref. The isolation from mosquitoes of 12 segmented dsRNA viruses antigenically related to BAV has been reported in various provinces of China, including Beijing, Gansu, Hainan, Henan, and Shanshi, and in central Java, Indonesia. BAV is now classified as a biosafety level 3 arboviral agent^ref.
Genomics : Seadornavirus has 7 structural proteins, 5 of which are present in the core^ref. The viruses are icosahedral with a diameter of 60–70 nm, and the core has a diameter of 50 nm. The surface of virus has spikes that are similar to those of rotaviruses. The viruses are stable at pH 7.0, and acidity decreases their infectivity (which is lost at pH 3.0). Purified virus can be stored at 4°C or for long periods at –80°C. Viral infectivity is decreased considerably upon heating to 55°C. Organic solvents such as Freon 113 or Vertrel XF can be used for purification of viral particles from cell lysates and do not affect infectivity. The seadornavirus genome consists of 12 segments of dsRNA known as Seg-1 to Seg-12 in order of decreasing molecular mass observed by gel electrophoresis. The genome of BAV or KDV is 21,000 bp, and the segment length ranges between 862 bp and 3,747 bp. During replication, viruses are found in the cell cytoplasm within vacuolelike structures that are believed to be involved in morphogenesis^ref. Seadornavirus isolates replicate in various mosquitoes cell lines such as C6/36 and AA23 (both from Ae. albopictus), A20 (Ae. aegypti), and Aw-albus (Ae. W. albus). > 40% of the virus particles are released into the culture medium before cell death and massive CPE (fusiform cells). Infected cells are not lysed, and the virus leaves cells by budding, thus acquiring a temporary envelope^ref. Late infection results in cell lysis from cell death. Intracellular radiolabeling of viral polypeptides has shown termination of host cell protein synthesis^ref. In addition to its capacity to replicate in a large number of mosquito cell lines, LNV is the only seadornavirus that replicates in a variety of transformed or primary mammalian cell lines such as Hep-2 (human carcinoma cells), BGM, Vero, BHK-21, L-929, and MRC-5 (human lung fibroblasts). Infection with LNV results in a massive lytic effect and also kills adult mice. Antigenic relationships between seadornaviruses were investigated by using mouse immune sera. BAV from southern China and Indonesia and KDV from Indonesia are classified as distinct species^ref and show no cross-reactivity in neutralization tests. These viruses are also antigenically distinct from LNV. Antigenic variations were observed in many isolates from China that showed cross-reactivity with BAV.Amino acid sequence analysis identified BAV, KDV, and LNV as 3 distinct species. Identities between homologous proteins ranged from 24% to 42%, with the highest value found in the polymerase gene. Analysis of different BAV isolates has shown the existence of 2 genotypes identified as genotype A (represented by isolates BAV-Ch [China] and BAV-In6423 [Indonesia]) and genotype B (represented by isolates BAV-In6969 and BAV-In7043 [Indonesia]). This grouping is based on sequences of segments 7 and 9: amino acid sequences of segment 7 show an identity of 72% between the 2 genotypes, while those of segments 9 show an identity of 41%. All other proteins among BAV isolates have identities ranging from 83% to 100%^{ref1, ref2}. Based on a seroneutralization assay, these 2 genotypes were found to represent 2 serotypes of BAV^ref. Sequence comparison of the structural proteins of BAV (VP1, VP2, VP3, VP4, VP8, VP9, and VP10) with those of other members of the Reoviridae have shown that VP9 and VP10 of BAV have similarities to VP8 and VP5 subunits of the outer coat protein VP4 of rotavirus A^ref. This finding was further confirmed when the crystal structure of BAV VP9 was determined and showed structural similarities to rotavirus VP8^ref. In addition, VP3 of BAV, which is the guanylyltransferase of the virus^ref, exhibited significant amino acid identity with the VP3 of rotavirus, which is also a guanylyltransferase. These data suggest an evolutionary relationship between rotaviruses and seadornaviruses
Transmission : Seadornaviruses have been isolated from Culex vishnui, Culex fuscocephala, Anopheles vagus, Anopheles aconitus, Anopheles subpictus, and Aedes dorsalis. Seadornaviruses were shown to replicate in adult laboratory mice and were detected in infected mouse blood at 3 days postinfection until day 5 postinfection^ref.
• Banna virus (BAV) is the type species isolated only from humans^ref
=> the only seadornavirus isolated from humans and associated with human disease is BAV. Persons infected with BAV exhibited flulike symptoms, myalgia, arthralgia, fever, and encephalitis (Xu P, Wang Y, Zuo J, Lin J. New orbiviruses isolated from patients with unknown fever and encephalitis in Yunnan province. Chin J Virol. 1990;6:27–33). A serologic diagnostic assay was developed^ref based on VP9, the outer coat protein responsible for cell attachment and neutralization. Patients infected with BAV have shown a 4-fold increase in anti-BAV antibody titers in paired serum specimens tested by ELISA, showing an immune response to the virus infection^ref. Molecular diagnostic assays have also been designed for detecting BAV and KDV^ref. RT-PCR assays were validated in infected murine model, in which the genome could be detected as early as 3 days postinfection. PCR assays identify differences between genotypes A and B of BAV based on the length of the amplicon obtained by specific primers in segment 9. A PCR assay was recently developed for LNV based on sequence of segment 12 that allows detection of the genome in infected mouse blood (H. Attoui, unpub. data).
Differential diagnosis : BAV, KDV, and LNV are found in tropical and subtropical regions where other mosquitoborne viral diseases, especially JE and dengue, are endemic. Several cases of encephalitis in China have been diagnosed as Japanese encephalitis (JE) without any detection of JEV or specific anti-JEV antibodies. Recently, 89 paired serum samples from these patients were tested by ELISA for anti-BAV IgG antibodies. At least a 4-fold (up to 16-fold) increase in IgG antibodies was observed in 7 cases. An additional 1,141 serum specimens of patients from a large number of health institutes in China, who supposedly had JE or viral encephalitis, were tested for anti-BAV IgM antibodies; 130 samples were positive^ref
Patients infected with BAV show a strong immunologic response (Li QP. First isolation of 8 strains of new orbivirus (Banna) from patients with innominate fever in Xinjiang. Endemic Dis Bull. 1992;7:77–82). Mice experimentally infected with BAV develop viremia. Clearance of the virus from the circulation occurs concomitantly with the appearance of anti-BAV antibodies^{ref1, ref2}
• Kadipiro virus (KDV) (isolated only from mosquitoes)
• Liao Ning virus (LNV) (isolated only from mosquitoes)
Melaka virus was isolated from a 39 year old male patient in Melaka, Malaysia, who was suffering from high fever and acute respiratory disease at the time of virus isolation. Two of his family members developed similar symptoms about one week later and had serological evidence of infection with the same virus. Epidemiological tracing revealed that the family was exposed to a bat in the house about one week before the onset of the father's clinical symptoms. Genome sequence analysis indicated a close genetic relationship between Melaka virus and Pulau virus, a reovirus isolated in 1999 from fruit bats in Tioman Island, Malaysia. Screening of sera collected from human volunteers on the island revealed that 14 of 109%) were positive for both Pulau and Melaka viruses. This is the 1st report of an orthoreovirus in association with acute human respiratory diseases. Melaka virus is serologically not related to the different types of mammalian reoviruses that were known to infect humans asymptomatically. These data indicate that batborne reoviruses can be transmitted to and cause clinical diseases in humans^ref.
Pathogenesis : infection of human intestinal epithelial cell induces calpain-dependent pIgR upregulation, an innate immune response against invading pathogens that could help the host clear infection effectively^ref
Therapy : no specific treatment exists for infections caused by any members of the family Reoviridae. Symptomatic treatment includes acetaminophen for relief of fever and pain.
Web resources : dsRNA Viruses
• ssRNA negative-strand viruses : only viral RNAs coated with nucleocapsid protein, a viral single-stranded RNA (ssRNA) binding protein, can be used as templates for RNA-directed RNA polymerase (RdRP)

Proteomics : viral G-addition RNA editing
• Arenaviridae : the arenaviruses: a family of RNA viruses having a pleomorphic virion 50–300 nm in diameter consisting of a lipid bilayer envelope, with large peplomers, surrounding a coiled nucleocapsid with two members and a variable number of ribosomes. The genome consists of 2 circular molecules of ambisense single-stranded RNA, designated L (MW 1.1 x 10⁶) and S (MW 2.2–2.8 x 10⁶) (size of total genome 10–14 kb). Viruses contain 3 major polypeptides, including a transcriptase, and are UV- and g radiation–sensitive. Replication and assembly occur in the cytoplasm; virions are released by budding through the plasma membrane. Host ranges are narrow. There is a single genus :
• Arenavirus (from the granules that give the virions a sandy appearance). Rodents are common hosts.
• 1-LCMV-LASV complex / Old World arenaviruses
• Lassa virus
• Lassa virus (STRAIN GA391)
• Lassa virus (strain Josiah)
Epidemiology : first described in the 1950s, although the virus was not isolated until 1969 when 2 missionary nurses died in Nigeria and the virus was named after the Nigerian town where the cases originated. Nowadays it is endemic throughout West and Central Africa. The most severely affected countries are in the Mano River Union (Guinea, Liberia and Sierra Leone (Kenema district is located in the south of Sierra Leone close to the border with Liberia)) and to a lesser extent Nigeria (an outbreak (6 deaths) has been reported in the northern part of the Nigeria's midwestern state of Edo, including Ekpoma, Igarra and Ibilo), Liberia, and Guinea). Cote d'Ivoire and Ghana are potentially at risk. The incidence of Lassa fever has been increasing in the affected areas. Civil unrest in the Mano River Union region created newly vulnerable populations, including refugees and humanitarian relief workers. There have been several recent fatal cases of Lassa fever among United Nations peacekeeping forces. The return of areas to government control and the rebuilding of civil society in Liberia and Sierra Leone puts aid workers at risk of contracting Lassa fever. In West Africa, Lassa fever causes 100,000 to 300,000 human infections and approximately 5000 deaths each year. In endemic areas of rural West Africa subclinical infection is common, but occasional outbreaks with high mortality rates have been recorded.
• Sierra Leone : Lassa fever is most common in the eastern region; 1-4 Mastomys are found in every household in this area, of which 1-20% are infected with Lassa virus. In some areas of eastern Sierra Leone, the disease accounts for 30% of medical death in-hospital, 30% of deafness and 70% of spontaneous abortion. 8-52% of the population are seropositive.
• Liberia : Lassa fever accounts for 10-20% of hospitalizations for fever, and is common throughout the country - with the highest incidence seen in Lofa, Nimba and Grand Cape Mount. Lassa fever in Liberia^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8}
Notable outbreaks:
• 1970-1972 : 63 cases were reported in Panguma-Tongo region (Eastern Province) during October 1970 to October 1972.
• 1995 : an outbreak (167 cases, 60 fatal) was reported in Kenema District -- most patients were adolescent females.
• 1996 : 799 cases (148 fatal) were reported, including 99 cases (13 fatal) from Kenema District during November and December.
• 1997 : 353 (43 fatal) cases were reported during January to April 1997.
• 2003 : an outbreak of suspected Lassa fever (80 cases, 8 fatal) was reported in the central region, with several cases reported in refugee camps.
• 2004 : an outbreak was reported in Kenema district.
There is also risk of transmission of disease when unrecognized Lassa fever cases are imported into non-endemic regions for treatment of haemorrhagic disease. Since 1970, at least 17 cases of imported Lassa fever have been reported outside of West Africa, often by persons returning from West Africa (Liberia, Nigeria, Ivory Coast, Chad, and Sierra Leone) :
• 1976 : a Peace Corps worker returned to the United States from Sierra Leone with Lassa fever.
• 1987 : an Israeli national acquired Lassa fever in Sierra Leone, and survived under treatment in Israel.
• 1989 : 1 died case in USA^ref
• 2000 :
• a British national acquired Lassa fever in Sierra Leone, and died while under treatment in England. The risk of further transmission to humans of Lassa fever in the UK from imported cases is extremely low, and the natural reservoir is not found in the UK. Risk is confined to those who have had direct physical contact with body fluids from the patient during the infectious period. There have been no recorded transmissions by such a route in the UK, including 74 health care worker contacts followed up by serology after the case in 2000^ref. There is no risk to the general public including travelling companions. A review of casual contacts that took place in the 1960/70s found no transmission among airline passengers travelling with confirmed Lassa cases^ref.
• a German student returning from Ghana and Cote d'Ivoire^ref.
• in the Netherlands^ref
• 2000 : a Dutch national acquired Lassa fever in Sierra Leone, and died while under treatment in the Netherlands.
• early September 2003 : a British soldier  acquired Lassa fever in Sierra Leone, and was treated successfully in the U.K.^ref
• 2004 : 1 died case in USA^ref
Transmission:
• a zooanthroponosis from food or water contaminated by urine from persistently infected Mastomys natalensis (multimammate mouse : usually without obvious signs of disease)
• interhuman contagion by blood or vomitus, particularly in hospital settings. The risk for human-to-human transmission of Lassa fever is low^{ref1, ref2}; however, healthcare-associated transmission has occurred in areas where Lassa fever is endemic, and one instance of asymptomatic seroconversion was reported in a European physician^ref. Meticulous adherence to appropriate infection-control practices to prevent unprotected exposure to blood or other body fluids is essential to the safe management of patients with possible Lassa fever and to the protection of health-care workers^ref. Family members and others visiting a hospitalized patient must be instructed to adhere to infection-control precautions and avoid exposure to potentially infectious blood or body fluids. In the absence of proven effectiveness, oral ribavirin prophylaxis was not recommended for persons who might have been exposed to the patient described in this report. Instead, a standard treatment regimen of intravenous ribavirin was recommended for any contacts with clinical evidence of infection during the incubation period. Because of the serious nature of the disease, vigilance is required in assessment and treatment of patients arriving with febrile symptoms from endemic areas.
• respiratory route is extremely poorly effective : early in the initial Nigerian epidemic, a nurse infected and ill with Lassa fever virus traveled from Nigeria to New York by air without transmission of the virus to other passengers or the airline crew.  In studies conducted in the 1960s and 1970s, there was no evidence of Lassa fever virus transmission to airline passengers traveling with confirmed Lassa fever cases^ref. Similarly, in 2004, 19 passengers on a flight from London to Newark, New Jersey, USA, with a Lassa fever virus-infected man returning from Liberia, were considered at low risk of exposure, and none became infected with the virus. On 21 Jul 2006 a 68-year-old man who traveled from Freetown, Sierra Leone to Germany via Belgium was diagnosed with Lassa fever^{ref1, ref2}. While awareness is indicated, care should be taken not to engender fear among the passengers.
Pathogenesis : readily engaged its cell-surface receptor α-dystroglycan in avian cells, but virus entry in susceptible species involved a pH-dependent switch to an intracellular receptor, the lysosome-resident protein LAMP1^ref
The incubation period ranges from 7 to 21 days :
=> 80% of human infections are subclinical or mild : common early symptoms are gradual onset of fever (lasting for 7-17 days), malaise, headache, and abdominal pain. Other symptoms are conjunctivitis, facial edema, pharyngitis, dry cough, retrosternal pain, nausea and vomiting, diarrhea, back pain, myalgia, and occasionally a maculopapular exanthema. Respiratory and pulse rates and temperature are increased and blood pressure decreased. Neurological symptoms may also occur, including sensorineuraldeafness (25-30% : may be permanent), tremors, and encephalitis
=> Lassa (hemorrhagic) fever: hemorrhagic manifestations (not usually evident) may include mucosal bleeding and, less frequently, conjunctival, gastrointestinal, or vaginal bleeding. Severe infections produce hemorrhagic manifestations, pleural effusions, a sudden drop in blood pressure on the seventh day, with death resulting from shock, systemic arterial hypotension, peripheral vasoconstriction, hypovolemia, and anuria
Differential diagnosis : severe malaria, typhoid fever, yellow fever and other viral haemorrhagic fever
Prognosis : approximately 15-20% of patients hospitalized for Lassa fever die from the illness, but the outcome can be improved by simple supportive care if provided early in the course of the disease; 1% of infections overall result in death^ref (pregnant women are more likely to die than are others)
Treatment is supportive and also includes ribavirin.
Prevention : VLP vaccine.
It is considered by CDC as a category A biological weapon.
• Lymphocytic choriomeningitis virus (LCMV)
• Lymphocytic choriomeningitis virus (strain Armstrong)
• Lymphocytic choriomeningitis virus (strain Pasteur)
• Lymphocytic choriomeningitis virus (strain Traub)
• Lymphocytic choriomeningitis virus (strain WE)
Epidemiology : isolated in 1933; affects mainly adults 20 to 40 years of age during the late winter months. Serologic studies conducted in urban areas of the USA have indicated that prevalence of LCMV infection among humans is approximately 5%^{ref1, ref2}. It has been estimated that about 8% of viral meningitis cases in the USA can be attributed to LCMV infection, but most LCMV infections are mild or subclinical and their incidence in the general population of the USA may be as high as 10-15%
Transmission :
• a zooanthroponosis from rodent secretions (commonly found in house mice worldwide^{Institute of Laboratory Animal Resources Commission on Life Sciences, National Research Council. Guide for the care and use of laboratory animals. Washington, DC: National Academy Press; 1996}).
• the house mouse (Mus musculus) is the primary reservoir for LCMV, with a prevalence of infection of 3-40%; a high degree of focality often is noted^{ref1, ref2, ref3}
• other types of rodents can be infected after contact with infected house mice^ref; these rodents also have been implicated in human infection.
• hamsters (Cricetinae)
• guinea pigs (Cavia porcellus)
• callitrichid (family: Callitrichidae), which are commonly exhibited in zoos and occasionally kept as pets. LCMV primarily targets the liver in these small South American monkeys, producing an acute fatal viral hepatitis with jaundice and milder lymphocytic meningitis. Callitrichid hepatitis (CH) broke out in zoos in the US in the 1980s and early 1990s and was associated mostly with the feeding of newborn mice as a dietary supplement. Wild mice were also implicated in some of the documented cases. Seroconversion to LCMV antibodies occurred in 2 individuals involved in some of the episodes (one of whom was an attending veterinarian) but with no history of clinical disease. The incidence declined significantly with recommended management practices of not feeding mice and improving rodent control in the zoo settings. Similar occurrences of CH have been reported in Germany^{ref1, ref2, ref3, ref4, Scanga, C.A., Holmes, K.V., Montali, R.J.: Serologic Evidence of Infection with Lymphocytic Choriomeningitis Virus, the agent of Callitrichid Hepatitis, in Primates in Zoos, Primate Research Centers, and a Natural reserve. J. of Zoo and Wildlife Medicine, 24(4):469-474, 1993}.
• marmosets
• tamarins
LCMV has been widely used in laboratories by virologists and immunologists and has played an important part in unraveling the complexities of viral immunology and immmunopathology. Doherty and Zinkernagel, in their Nobel prize-winning work, used an LCMV-mouse model to demonstrate the important concept of MHC class I restriction in cytotoxic T cell recognition. Outbreaks of human infection have been recorded in laboratories, and, as a consequence, a laboratory-adapted strain with reduced hazard for humans is commonly used in laboratories now.
Animals can become ill or can be asymptomatic. Although other animals could possibly become infected with the virus, documented infections in humans have occurred only after exposure to infected mice, guinea pigs, and hamsters^{ref1, Traub E. The epidemiology of lymphocytic choriomeningitis in white mice. J Exp Med 1936;64:183--200}. Infection in humans occurs primarily through exposure to secretions or excretions of infected animals^ref. A large outbreak associated with pet hamsters sold by a single distributor was reported in 1975, when 181 symptomatic cases among persons with hamster contact were identified in 12 states; no deaths occurred^ref. The outbreak was brought under control by voluntary cessation of sale and destruction of the infected breeding stock. In mice the virus is maintained both by vertical transmission in utero and via the gastrointestinal tract. Rodent-to-human transmission probably occurs via aerosols and fomites. Unmanipulated mice all succumb to lethal choriomeningitis within 7 days after LCM i.c. inoculation. Death is caused by excessive immunopathology due to the antiviral CD8 response and depends on lytic effector function as well as IFN-g production. Importantly, mice that are harboring LCMV-specific memory lymphocytes at the time of i.c. infection will survive, because viral spread is limited more rapidly by memory effectors. Conversely, mice without LCMV memory will only survive the more widespread i.c. infection if antiviral immunity is inhibited, for example by depleting CD8 CTL. The potential tradeoff is lack of viral clearance and persistent infection if immunity is lowered beyond a certain threshold. Persistent LCMV infection of the brain, however, will cause no major clinical problems, since LCMV is a non-lytic virus. LCMV clone 13 (LCMV Cl 13), in contrast to LCMV strain Armstrong, causes a long-term persistent infection in mice that is cleared from serum over the course of 2-3 mo : it induces host immunosuppression by inhibiting DC development (impaired expansion in response of DC populations in response to in vivo administration of Flt3 or in vitro treatment with GM-CSF), maturation, and T-cell proliferation in a MLR (downregulationof the cell-surface expression of MHC class I and II molecules and the co-stimulatory molecules CD40, CD80 and CD86) mediated by type I IFNs^ref. LCMV infection is a well-known occupational risk for laboratory workers who work with LCMV-infected laboratory rodents^ref
• human-to-human transmission of LCMV has not been reported, with the exception of vertical transmission from an infected mother to fetus^{ref1, ref2}.
• solid organ transplantation :
• in 2003, a cluster of solid organ transplant-associated meningoencephalitis deaths in Wisconsin was investigated and determined to be associated with LCMV infection. In that investigation, testing of donor tissues did not reveal any evidence of infection (Paddock C, Ksiazek T, Comer JA, et al. Pathology of fatal lymphocytic choriomeningitis virus infection in multiple organ transplant recipients from a common donor. Mod Pathol 2005;18(Suppl):263A--4A), and no exposures to rodents were found.
• in early April 2005, in Rhode Island, USA, a woman with a medical history remarkable only for hypertension and one week of headache had sudden onset of hemiplegia caused by a stroke, followed by brainstem herniation and brain death within 3 days. A thorough evaluation was not suggestive of infection. Family members of the woman consented to donation; organs and tissues were recovered, including the liver, the lungs, both kidneys, both corneas, and skin. Within 3 weeks after transplantation, the 4 persons who received the liver, lungs, and 2 kidneys had abnormalities of liver function and blood coagulation, and dysfunction of the transplanted organ. Signs, symptoms, and clinical laboratory test results varied in these patients and included fever, localized rash, diarrhea, hyponatremia, thrombocytopenia, hypoxia, and kidney failure. 3 of the 4 organ recipients died, 23 to 27 days after transplantation. The 4th patient, a kidney recipient, survived. Histopathologic findings varied in the 4 cases, but hepatocellular necrosis was common to all 3 decedents on autopsy. The 2 cornea recipients were asymptomatic. Skin was not transplanted. When the cause of illness among the recipients was not identified through extensive diagnostic testing and suspicion of transplant-transmitted infection arose, tissue and blood samples from the donor and recipients were sent from the Rhode Island Department of Health and the Massachusetts Department of Public Health to CDC. LCMV was identified as the cause of illness in all 4 organ recipients; diagnosis was made in tissues from multiple organs through immunohistochemical staining, RT-PCR, ELISA (i.e., IgM capture and indirect IgG), and viral culture on Vero E6 cells. Sequencing of the virus genome confirmed its identity as LCMV. Based on the diagnosis of LCMV infection, the surviving kidney transplant recipient was treated with intravenous ribavirin and reduction in his immunosuppressive drug regimen; the patient improved clinically. Interviews with family members of the donor determined that a pet hamster had been acquired recently. The hamster was cared for primarily by another family member. Family members of the donor were tested for LCMV antibodies. The family member who cared for the hamster had specific IgM and IgG antibodies to LCMV. No other family member had detectable IgG or IgM antibodies to LCMV. All available donor tissues were tested, and no evidence of LCMV was determined by serology, IHC, RT-PCR, or viral culture. However, the pet hamster was determined positive for LCMV by virus isolation, RT-PCR, and immunohistochemistry. Genetic sequencing to enable comparison of patient and rodent virus isolates is planned. Public health officials announced the deaths on Mon 23 May 2005. There are no plans to begin testing other donor organs for the virus since it is so rare and testing could take several days, potentially making the organs unusable. He said he believed there was no commercially available test for the virus. Only one previous instance of LCMV causing a transplant-related death has been reported -- in Wisconsin in December 2003 -- but it wasn't definitively linked to rodent exposure. CDC investigators were testing the dead hamster, purchased at a Warwick pet shop, to confirm the virus as the cause of the recent deaths. The Petsmart pet shop where the donor bought the hamster has stopped selling mice and hamsters and has given its import and sales records to the state Department of Environmental Managemen. Jennifer Pflugfelder, spokeswoman for Phoenix-based Petsmart, said the CDC took away about 60 hamsters, mice, and rats last week, and the remaining animals were taken from the shop Mon morning, she said. She didn't know how many were removed altogether
• in May 2005 a distributor (where 3% of hamsters were infected) supplied a local pet store with at least 4 LCMV-infected rodents (3 hamsters and a guinea pig) : 1 of the hamsters was purchased by a man which later become an organ donor. The 4 recipients were infected^{ref1, ref2}
Pathogenesis : during LCMV infection, CD27 signaling on CD4⁺ T cells enhances the secretion of IFN-g and TNF-a. These inflammatory cytokines lead to the destruction of splenic architecture and immunodeficiency with reduced and delayed virus-specific neutralizing antibody responses. Consequently, infection with the otherwise persistent LCMV strain Docile was eliminated after CD27 signaling was blocked^ref
=> lymphocytic choriomeningitis (LCM) / Armstrong's disease after 3-13 days incubation => usually asymptomatic or mild self-limited flu-like syndrome, characterized by any or all of the following symptoms: fever, malaise, lack of appetite, muscle aches, headache, nausea, and vomiting => hematogenous spread => choriomeningitis for 8-10 days : lethal in immunosoppressed patients or self-limiting within 15-20 days^ref
=> infection during pregnancy can result in vertical transmission of the virus from mother to fetus; LCMV infection during the 1st or 2nd trimesters can cause severe illness or developmental defects in the fetus, including hydrocephalus, psychomotor retardation, and blindness^ref; the proportion of developmental defects caused by LCMV is not known. It has also been associated with neurological illness and miscarriage in pregnant women^ref
Prevention : persons can minimize risk of LCMV infection from pet rodents by being attentive to proper hand hygiene and environmental cleaning^{ref1, ref2, ref3}
• control of wild rodents : environmental modifications and hygiene practices that deter rodents from colonizing the home and work environment are the best means of reducing risk for exposure to infectious rodents. In addition, if rodents are found in work or living areas, safe practices for cleaning rodent waste and nesting materials are recommended. Preventing wild rodent entry also reduces opportunity for infection of pet rodents.
• general recommendations for preventing LCMV infection from pet rodents : hamsters and other rodents are common pets, and the number of documented human LCMV infections from pet hamsters and other rodents is low. Basic precautions can reduce the risk for acquiring LCMV and other infections from pet rodents. Because rodents might not always exhibit signs of ill health resulting from LCMV infection, CDC recommends taking appropriate precautions with any rodent:
• the public should be apprised of the risk for LCMV infection from rodents purchased from any pet store.
• destruction or return of recently purchased pet rodents is not recommended.
• the probability of any one animal harboring LCMV infection is low. All pets are potential carriers of infectious diseases and should always be handled by using appropriate precautions.
• pet rodents must not be released into the wild to prevent introduction of nonnative species to North America.
• persons with specific concerns regarding the health of their pets should seek guidance from a veterinarian.
Anyone handling or keeping pet rodents should take the following precautions to reduce the risk for LCMV infection:
• wash hands with soap and water (or alcohol-based hand sanitizers when soap is unavailable and hands are not visibly soiled) after handling pet rodents or cleaning up pet droppings, cages, or areas where pets have been.
• keep rodent cages clean and free of soiled bedding.
• clean cages outdoors or in a well-ventilated area.
• closely supervise young children when cleaning cages or handling rodents and supervise or assist children in washing their hands immediately after handling rodents and rodent cages or bedding. Never kiss or hold pet rodents close to the face.
• never allow pet rodents to come into contact with wild rodents or their droppings or nests. Cover pet rodent cages and food supplies and always supervise pet rodents when they are not in their cages.
Pet Stores with Potentially Infected Rodents in Stock : 2 national retail chains have temporarily stopped the sale of potentially affected rodents (e.g., hamsters, guinea pigs, gerbils, rats, chinchillas, and mice) originating from MidSouth Distributors since February 2005. Pet stores that have received rodents from MidSouth Distributors since February 2005 should contact the appropriate authority in their states (i.e., state health department or state department of agriculture) for additional information and guidance. Although LCMV is known to infect hamsters and guinea pigs, data are insufficient to determine the potential for infection of other rodent species (e.g., chinchillas, dwarf hamsters, or gerbils). However, husbandry practices in breeding facilities, distribution centers, and pet stores make cross-contamination with LCMV of other species a possibility. CDC is working with retailers in the pet industry to consider appropriate testing of these other rodent species. Practices that can lead to cross-contamination of rodents include
• housing healthy rodents in the same room or bin or in cages near potentially infected rodents (i.e., rodents from the MidSouth Distributors facility in Ohio)
• handling or caring for rodents without washing hands or changing gloves after handling other rodents and between other animal-care activities, such as cleaning cages
• placing rodents in cages that previously housed other rodents without 1st decontaminating the cages with bleach or other appropriate disinfectants
• reusing materials (e.g., water bottles, food dishes, bedding, or toys) that might be contaminated by potentially infected rodents.
Pet rodents that did not originate from MidSouth Distributors of Ohio and were not exposed to potential ross-contamination can be sold or distributed as normal. In addition, non-rodent species (e.g., ferrets and rabbits) can be sold or distributed as normal. Pet stores are advised to work with state authorities to minimize the risk for transmission of LCMV from affected rodents to humans. Options considered by state authorities include :
• stopping sale or distribution of all rodents originating from MidSouth Distributors of Ohio since February 2005
• stopping sale or distribution of hamsters and guinea pigs originating from MidSouth Distributors of Ohio since February 2005
• allowing distribution (i.e., sale or adoption), provided that appropriate educational material (e.g., state-approved informed consent or fact sheet) is provided to purchasers of pet rodents originating from MidSouth Distributors since February 2005.
Educational material should disclose the specific LCMV risk in this population of pet rodents and potential outcomes in humans, including birth defects and fetal deaths. If sale of rodents is allowed to continue, populations at high risk (i.e., pregnant women, women who think they might become pregnant, and persons with weakened immune systems) should be advised against purchasing a pet rodent^ref. Preventing LCMV infection in new supplies of rodents : efforts are under way to ensure that animal facilities and equipment in retail outlets are disinfected, that new supplies of rodents come from sources free from LCMV, and that cross-contamination between new supplies of rodents and potentially infected animals will not occur. Surfaces, cages, and any reusable equipment that has been in contact with affected animals, their waste, or bedding material should be cleaned and disinfected by using a household disinfectant according to the manufacturer's instructions. Persons who are pregnant or have compromised immune systems should not engage in cleaning and disinfection related to these affected animals or other rodents. CDC and other partners will work with breeders and retailers in the pet industry to implement quality-assurance programs to minimize the risk for LCMV infection in rodents that are sold to the public.
Previously purchased pet rodents : testing of individual pet rodents in households is not a recommended strategy to minimize risk for LCMV infection; the probability of any one rodent in the United States being infected is low. The greatest infection risk for a pet owner is likely to occur soon after purchase of a pet rodent. Thus, most exposures likely already have occurred for existing owners and substantial added risk is unlikely to result from continued ownership of the rodent. However, women who are or who plan to become pregnant and persons who are immunocompromised should avoid contact with all rodents. To prevent any possible infection of other rodents in stores, owners should not return pet rodents from MidSouth Distributors to pet stores. For legal, ethical, and wildlife conservation considerations, owners should not release pet rodents into the wild. Persons who no longer wish to keep their pet rodent should consult a veterinarian. CDC continues to work with state public health officials and retailers in the pet industry to educate the public regarding safe handling of pet rodents and has prepared educational material for reducing the risk for LCMV infection from pet rodents. Rodents and other pets from any pet store pose some risk for transmitting certain infectious diseases and should be handled appropriately.
• precautions for pregnant women : although the risk for LCMV infection from pet rodents is low, pregnant women or women who think they might become pregnant should be aware of the risks associated with LCMV infection during pregnancy. The following precautions can be taken to reduce the risk for acquiring LCMV infection during pregnancy:
• avoid contact with wild rodents. Pregnant women who reside in a household with a wild rodent infestation should have the infestation addressed promptly by a professional pest control company or another member of the household.
• keep pet rodents in a separate part of the home. Pregnant women should ask another family member or friend to clean the cage and care for the pet or arrange for temporary adoption of the pet by a responsible person. Pregnant women should avoid prolonged stays in any room where a rodent resides.
• precautions for persons with weakened immune systems : for the organ recipients described in this report, transplantation of LCMV-infected organs into persons with medically induced immunosuppression likely increased disease severity. Persons with impaired immune-system function should avoid contact with all rodents.
• testing for LCMV in pet rodents : CDC does not recommend testing pet rodents. Serologic testing on rodents can be inaccurate and misleading. All pet animals should be assumed capable of transmitting certain infectious diseases.
• testing for LCMV in humans : testing for LCMV infection in asymptomatic persons is not necessary. Similarly, testing persons with previous history of LCMV-compatible illness generally is not useful. Persons with active disease suggestive of LCMV should seek medical care and report any exposures to wild or pet rodents. A physician should determine whether testing for LCMV is indicated. Physicians should work closely with their respective state health departments to discuss forwarding of samples to state laboratories or CDC for testing
The major problem is the assumption that personal protective measures will protect owners of LCMV-infected pets from infection. There can be disastrous consequences of infection of the fetus of an exposed woman, and potentially of all immunosuppressed persons, so that definitive protection against infection is mandated. Although the incidence of central nervous system disease after LCMV infection of the average person is unknown, the disease is not trivial when it occurs, and an antibody prevalence of approximately 5 percent in the general population suggests there are quite a number of infections. The recommendations listed certainly would reduce the risk of infection if one were working with infected animals, but would not be considered at all adequate for laboratory or animal care of known infected animals.  In particular, the recommendation to "Closely supervise young children when cleaning cages or handling rodents" is ridiculous. The LCMV-infected rodent should not be sold to pet stores or passed along to consumers. LCMV is a chronic, vertically transmitted infection of house mice (Mus musculus), and no other host supports it as a chronic infection. In commercial breeding colonies, horizontal infection with chronic virus excretion among hamsters can be sustained, but this form of infection is not known among wild rodents. Guinea pigs suffer fatal infection, but the outcome of LCMV infection in gerbils and other potential pet rodents is not well-documented. Thus, the key element for keeping mouse and hamster colonies free of LCMV is to establish known "clean" colonies and exclude contact with wild Mus, so that the colonies cannot be infected in this way.  Because of the difficulty of definitively excluding wild Mus, periodic testing of colonies should be carried out to assure virus is not introduced. This is the norm for breeders of mice and hamsters for scientific use, but there are no statutory requirements for pet animals. The norm for LCMV infection among animals in colonies should be 0% infection and anything less than this is both irresponsible and unacceptable. It is important to recognize that the goal of maintaining LCMV-free mouse and hamster colonies is readily achievable and has been accomplished by the scientific suppliers. One also has to appreciate the biology of LCMV; it is uniquely linked to wild house mice, the control point. The potential for aerosol transmission is high and thus measures to reduce human contact with fomites cannot by themselves provide safety. Contrast this with the relation between Toxoplasma gondii and domestic cats. It is virtually impossible to rid felines of this highly infectious human pathogen, and the strategy for protection of humans (and the highly sensitive fetus) does involve the kind of protective measures suggested. We strongly urge the adoption of measures to assure that breeding centers for pet animals be properly tested for LCMV infection, that animals sent from infected colonies be traced and destroyed, and that we be able to assure a source of pet rodents safe from infection with virus. The tragedy of fetal infection with LCMV and the morbidity from this virus can be reduced to virtually zero. Callitrichid (marmosets and tamarins) hepatitis occurred in zoos in the US in the 1980s and early 1990s and was associated mostly with the feeding of newborn mice as a dietary supplement. In these cases, newborn mice were not obtained from sources known to be properly controlled against LCMV infection. Wild mice were also implicated in some of the documented cases^ref. In specific criticism of the CDC report, we point out the phrase "the prevalence of LCMV in pet rodents is not known."  Perhaps not specifically, for each pet shop, but it is known that LCMV is vertically transmitted, and this mechanism leads to the high excretion state, whereas horizontal transmission between adult mice leads to limited infection without chronic viremia, which Traub recognized > 60 years ago. Infection beyond the major colonies would be horizontal and thus not be a problem with mice. It could be more of a problem with hamsters, but would be more likely to lead to overt disease^{ref1, ref2, ref3}. The colonies could be monitored easily. Studies during outbreaks in the past show that infection can occur when infected animals are kept in homes even without direct contact, and laboratory workers have been infected (presumably by aerosols) after only a single entrance into a laboratory^{ref1, ref2, ref3}. The bottom line is that there appears to be a lack of political will to take the necessary steps.  Telling people (who likely will never see the recommendations) to "be careful" and not mentioning that close supervision of young children when cleaning cages or handling rodents is essentially irrelevant or that it would be better to have strict surveillance of the hamster (or any pet), rather than the child, seems irresponsible.  The best solution is to legislate requirements for pet shops and other sources of rodents or to eliminate these sources of disease altogether and suggest acquiring a real pet or go to a baseball game. Half a century of experience with LCMV plus the repeated experiences with nfectious agents found among prairie dogs (tularemia, monkeypox, plague, hantaviruses) should have changed the landscape in all this but obviously has not.
• 2-Tacaribe virus (TACV) complex/ New world arenaviruses^ref
• lineage A
• Flexal virus
• Parana virus
• Pichinde virus : infects Rodentia in Colombia, and isolated from human subclinical infections.
• Tamiami virus

Epidemiology : originally isolated from bats in Trinidad
=> it has been serologically linked to human infection
• lineage B : highly pathogenic
• Amapari virus (AMAV)
• Guanarito virus

Epidemiology : first isolated from patients in Guanare, Portuguesa state, west central Venezuela, primarily in settlers moving into areas of cleared fores
=> Venezuelan hemorrhagic fever : a zooanthroponosis (reservoirs : Sigmodon alstoni, Sigmodon hispidus and Oryzomys spp.). After 7-16 days incubation : fever, chills, myalgia, nausea and vomiting, generalized lymphadenitis, shock, oligoanuria, DIC, hemorrhages, neurological disorders => death (5-30%)
• Junin virus

Epidemiology : agricultural field hands in northern Argentina
=> Junin fever / Argentine or Argentinian hemorrhagic fever: a zooanthroponosis (contact with the excreta of infected reservoirs Calomys laucha and Calomys musculinus). After 7-16 days incubation : high fever, chills, leukopenia,thrombocytopenia, generalized myalgia, nausea and vomiting, generalized lymphadenitis, exanthema, shock, oligoanuria, DIC, hemorrhages, neurological disorders => death (5-30%)
Prevention : vaccine
• Machupo virus

Epidemiology : rural areas of northeastern Bolivia, emerged in the early 1960s as humans increasingly settled land east of the Andes. Originally a disease of rural areas, has spread more widely. San Joaquin community, next to Magdalena, had a quarantine declared in 1958, while in 1971, Viedma Hospital in Cochabamba was closed because of the occurrence of this disease
Transmission :
• a zooanthroponosis (reservoirs : Calomys callosus). Mice acquire the virus when they are newly born, and during the lactation period they start shedding it through their urine and saliva; they have permanent asymptomatic viremia. When Calomys mice acquire the virus in the adult stage, they may develop immunity; and, after a short period when they shed the virus, viral shedding stops. The virus causes persistent infection of its rodent host accompanied by abundant shedding of virus in urine, saliva and feces, which are the sources of infection for rodents and humans alike. In its natural host, Machupo virus eventually causes hemolytic anaemia as well as fetal death)
• interhuman transmission
=> Bolivian hemorrhagic fever / "black typhus" : after 7-16 days incubation : fever, chills, myalgia, nausea and vomiting, generalized lymphadenitis, shock, oligoanuria, DIC, hemorrhages, neurological disorders => death (5-30% in untreated cases). It is considered by CDC as a category A biological weapon
• Sabia virus
Epidemiology :
• isolated from a fatal case of hemorrhagic fever in São Paulo, Brazil
• lab infection
• the 1st lab infection was in a lab technician involved in isolating and identifying the prototype strain in Brazil (1992 or 1993?). No spread to other lab or hospital staff was seen^ref
• in 1994 a tube containing concentrated Sabia virus broke in a centrifuge at the Yale Arbovirus Research Unit. The centrifuge did not have screw-top caps on the buckets, so the contents of the tube were sprayed around the interior of the machine. The researcher cleaned it up as best he could, but became infected. While in the incubation period of the disease, before feeling very ill but probably already infectious, he attended a conference in the USA attended by a large number of people. Not one of them became infected, and neither did any of the staff who attended him at the hospital during his illness. He made a full recovery^ref.
Transmission : the reservoir is unknown but assumed to be a rodent.
=> Brazilian hemorrhagic fever. After 7-16 days incubation : fever, chills, myalgia, nausea and vomiting, generalized lymphadenitis, shock, oligoanuria, DIC, hemorrhages, neurological disorders => death (5-30%).
Tacaribe virus : isolated from bats in Trinidad, it is immunologically related to the Junin and Machupo viruses
• lineage C
• Latino virus
• Oliveros virus
• Quaranfil virus : an arbovirus found in Egypt, where it was isolated from the blood of children with febrile disease, from the blood of young egrets, and from ticks (Argas arboreus and Argas hermanni). It is ether-sensitive and presumed to contain RNA
• Bunyaviridae : the bunyaviruses: a family of RNA viruses having a spherical or oval virion 80–120 nm in diameter consisting of a lipid bilayer envelope, with glycoprotein surface projections 5–10 nm long and 10–12 nm across in hexagonal arrangement, surrounding 3 loosely helical nucleocapsids. The genome consists of 3 molecules of circular negative-sense or ambisense single-stranded RNA, designated L, M, and S (total MW 4.8–8 x 10⁶, size of total genome 11–20 kb). Viruses contain 4 major structural polypeptides, including a transcriptase, and are sensitive to lipid solvents and detergents. Replication occurs in the cytoplasm and assembly is by budding through the smooth membrane of the Golgi apparatus. Host ranges vary; transmission is generally by arthropod vectors, although transmission by aerosols and avian vectors sometimes occurs. Any segmented genome virus has the potential to generate a novel disease-producing virus by reassortment of genome sub-units from viruses not recognized to be serious human pathogens
• Hantavirus cause epidemic hemorrhagic fever or pneumonia, comprising at least 20 species included in one serogroup and unclassified species. Each species appears to have a single rodent species as a host (except for TPMV, which has an insectivore as a host!); transmission to humans is believed to be by contact, direct or indirect, with the excreta of infected rodents. 389 cases reported in USA since 1993 : cases of HPS have also been reported in Argentina, Bolivia, Brazil, Canada, Chile, Panama, Paraguay, and Uruguay, making this syndrome a pan-American zoonosis^{ref1, ref2}. Unlike viruses of the other genera of the family Bunyaviridae, the hantaviruses are not transmitted by arthropods
• Andes virus (ANDV)
• Bermejo virus

Epidemiology : Argentina
• Oran virus

Epidemiology : Argentina
Epidemiology : characterized in Argentina in 1995 on the basis of specimens from a patient who died of HPS^{ref1, ref2}, as been responsible for most HPS cases recorded in southwestern Argentina to about 50° south latitude, Chile (during 2003, 56 cases were registered in Chile; Region VIII was the most affected, with 21 cases. There were 19 deaths, representing a mortality rate of 29%, the lowest since 1997, when hantavirus infection was first recorded), and Uruguay^ref. 6 different ANDV lineages have been reported to cause HPS in Argentina: ANDV Sout in the southwest region; ANDV Cent BsAs, ANDV Cent Lec, and ANDV Cent Plata in the central region; and ANDV Nort Orán and ANDV Nort Bermejo in the northwest region. The definition of these 6 lineages was previously established on the basis of nucleotide and amino acid differences^{ref1, ref2}
Genomics : one fully sequenced human isolate of Andes virus (CHI-7913) exhibits an overall protein similarity of 92% with Sin Nombre virus but hemorrhage and renal involvement are common in these patients, features not often described in the North American literature on Sin Nombre virus-associated HPS
Transmission : reservoir : Oligoryzomys longicaudatus. Viral person-to-person transmission of ANDV Sout lineage was described for the first time during an HPS outbreak due to ANDV Sout lineage in southwest Argentina in 1996, in which 16 persons were involved^{ref1, ref2, ref3}, but in general, clusters of HPS cases are mainly attributed to a common source of rodent exposure. This mechanism of interhuman virus spread, which makes ANDV unique among the hantaviruses, is not the only exclusive feature of this virus. ANDV was the only American hantavirus isolated from human serum^ref. Most importantly, ANDV was shown to be highly lethal in Syrian hamsters, and the characteristics of the disease closely resembled HPS in humans^ref. Similar results have been recently obtained with Maporal virus^ref and ANDV Cent BsAs^ref. It occurs during the prodromal phase or shortly after it ends
Symptoms & signs : the term hantavirus cardiopulmonary syndrome (HCPS) is preferred by some as clinical differences may be observed in patients with hantavirus pulmonary syndrome caused by different hantaviruses. The term HCPS was originally adopted by clinicians who were caring for patients with HCPS at the University of New Mexico Health Sciences Center -- which remains by far the largest referral center in North America for patients with hantavirus diseases. Clinicians at referral centers were concerned because some of the primary care providers from whom they received referrals displayed a less than thorough degree of awareness that mortality due to HCPS is nearly always due to cardiac insufficiency. This deficiency in understanding of the pathogenesis of HCPS was often manifest as a failure to support cardiac function with inotropes and other cardioactive drugs, and/or a failure to understand the advantages of referring patients with HCPS to a center that offers adult extracorporeal membrane oxygenation (ECMO). In contrast to mechanical ventilation, which is available at any referral center, ECMO offers the distinct advantage of supporting patients whose cardiac function is markedly impaired by disease, as is almost universal in patients with severe "HPS". The intensive care unit physicians hoped that the adoption of the nomenclature "hantavirus cardiopulmonary syndrome" would improve the understanding among referring physicians of the importance of providing cardiac support for patients with HCPS. This hope may be justified, as referring physicians appear to be more aware of the cardiac manifestations of HCPS in the wake of the use of the term by referral center providers. In the case of Andes virus infection, renal insufficiency and muscle inflammation are observed more frequently than is the case with Sin Nombre virus infection in North America
• Bayou virus
Epidemiology : eastern Canada and eastern and southeastern United States
Transmission : reservoir : Oligoryzomys palustris
Symptoms & signs : the only hantavirus which causes hemorrhages
• Calabazo virus
Transmission : reservoir : Zygodontomys brevicauda in Panama
=> not associated with HPS
• Cano Delgadito virus
Transmission : reservoir : Sigmodon hispidus in northern Colombia
• Choclo virus
Epidemiology : Panama
Transmission : reservoir : Oligoryzomys fulvescens^ref
• Dobrava-Belgrade virus
• Saaremaa virus
Epidemiology : Balkans and northeastern France : originally isolated as Dobrava virus in Slovenia and Belgrade virus in Yugoslavia
Transmission : reservoir : Apodemus flavicollis and Apodemus sylvaticus)
=> severe epidemic hemorrhagic fever
• Four Corners hantavirus
Transmission : reservoir : Peromyscus maniculatus
• Hu39694 virus
Epidemiology : Argentina
Transmission : reservoir : ?
• Juquitiba virus
Epidemiology : Brazil
• Laguna Negra (LN) virus
Epidemiology : Bolivia and Paraguay
Transmission : reservoir : Calomys laucha (virus isolates obtained from two of these rodents were the first successful isolations of a pathogenic South American hantavirus. Analysis of the prototype LN virus entire S and M and partial L segment nucleotide and deduced amino acid sequences showed that this virus is unique member of the Sigmodontinae-borne clade of hantaviruses^ref)
• Lechiguanas virus
Epidemiology : Argentina
Transmission : reservoir : Oligoryzomys flavescens
• Mononghela virus
Epidemiology : eastern Canada and eastern and southeastern USA^ref
• New York hantavirus
Epidemiology : eastern Canada and eastern and southeastern USA
Transmission: reservoir : Peromyscus leucopus
• Rio Mamore virus (RIOMV) was first described in 1996 in Bolivia; it was associated with the small-eared pygmy rice rat, Oligoryzomys microtis^ref. Subsequently, 1 strain of RIOMV was isolated from O. microtis rats in Peru, designated HTN-007^ref; and 2 strains were recovered in the Brazilian Amazon from O. microtis rats (RIOMV-3) and uncharacterized species of rodents of the genus Oligoryzomys (RIOMV-4)^ref. Recently, HPS cases associated with RIOMV have been reported: 2 cases in Peru (Casapía M, Mamani E, García MP, Miraval ML, Valencia P, Quino AH, Hantavirus pulmonary syndrome (Rio Mamore virus) in the Peruvian Amazon region [in Spanish]. Rev Peru Med Exp Salud Publica. 2012;29:390–5) and 1 case in French Guiana (caused by a variant named Maripa virus)^ref. From a patient with fatal HPS in Brazil^ref
• Rio Segundo virus
Transmission : reservoir : Reithrodontomys mexicanus in northern Colombia
• Sin Nombre virus (a.k.a. Muerto Canyon virus)
• Convict Creek 107 virus
Epidemiology :
• North America, from Alaska to Mexico (expecially southwestern USA, the predominant cause of HPS in the USA and Canada). Since the virus was discovered in the Four Corners area (Arizona, Colorado, New Mexico, and Utah) in May 1993, a total of 465 laboratory-confirmed cases of HPS has been recorded with a mortality rate of 35%, in the USA, including 32 retrospectively identified cases that occurred before 1993^ref. 62% have been male, 38% female. The mean age of confirmed case patients is 38 years (range: 10 to 83 years). HPS can strike anyone; however, whites currently account for 78% of all cases. American Indians account for about 19% of cases, African Americans for 2% of cases, and Asians for 1% of cases. About 13% of HPS cases have been reported among Hispanics (ethnicity considered separately from race). Cases have been reported in 31 states, the majority of cases in the Southwest. Most cases have occurred in southeastern and western states^ref :
• Arizona 37
• California 42
• Colorado 37
• Florida 1
• Idaho 18
• Illinois 1 (one dead man in 1996 and one in 2005 ?)
• Indiana 2
• Iowa 6
• Kansas 12
• Louisiana 1
• Massachusetts 1
• Minnesota 2
• Montana 24
• Nebraska 6
• Nevada 15
• New Mexico 74 (including 31 deaths) : 1 case in 2005, 4 in 2004, 8 (3 of them fatal) in 2006
• New York 1
• North Carolina 1
• North Dakota 7
• Oklahoma 2
• Oregon 5
• Pennsylvania 4
• Rhode Island 1
• South Dakota 9
• Texas 26
• Utah 24
• Vermont 1
• Virginia 2
• Washington 28
• West Virginia 1
• Wisconsin 1
• Wyoming 6
• Unknown 3
Subclinical infections are rare, according to antibody prevalence studies performed after the 1993 outbreak^{ref1, ref2, ref3}. The distribution reflects a spring-summer seasonality for identified cases, although cases occur throughout the year. Cases have been reported in 30 states, including most of the western half of the country and some eastern states as well. Over half of the confirmed cases have been reported from areas outside the Four Corners area. About 3/4ths of patients with HPS have been residents of rural areas^{ref1, ref2}.
• Canada : a man from Nicolet contracted the disease in a forest just north of Trois-Rivieres in 2004^{ref1, ref2}.
Transmission : inhalation of infected Peromyscus maniculatusdroppings
=> all the abovementioned viruses cause the hantavirus pulmonary syndrome (HPS). Incubation ranges from 7-14 (up to 43) days. The clinical presentation of an individual with Sin Nombre virus infection has 2 phases. The first is a prodromal period averaging about 4 days in length where infected individuals complain of non-specific "flu-like" symptoms which almost always include fever, and often include headache, cough, sore muscles and joints, nausea, vomiting or diarrhea. Laboratory testing for specific evidence of Hantavirus at this stage is not currently available. Following the prodromal phase, the clinical situation evolves rapidly with continued fever and the development of severe respiratory distress. Non-cardiogenic pulmonary edema, hypotension and respiratory distress syndrome ensue and require prompt admission to hospital.
Laboratory examinations : serological, immunohistochemical, and PCR testing, leukocytosis, hemoconcentration, and thrombocytopenia; bilateral pulmonary interstitial infiltrates are seen on x-ray
Treatment is supportive and is focused on maintaining adequate oxygenation and blood pressure, and on avoiding fluid overload. Administration of Ribavirin, although utilized, has not been clearly demonstrated to be helpful. Ventilation may be necessary within 24 hours of onset
Prognosis : without hospitalization and intensive care support death may follow within 9 days (lethality : 50%)
Prevention : Mills, J. N.,  T. L. Yates, J. E. Childs, R. R. Parmenter, T. G. Ksiazek, P. E. Rollin, and C. J. Peters. 1995. Guidelines for working with rodents potentially infected with hantavirus. Journal of Mammalogy 76:716-722 . Hantavirus particles are enclosed in a lipid layer that can be broken down by most disinfectants. Thus, dilute hypochlorite solution (1:10 household bleach with water), detergents, ethyl alcohol (70%) and most general purpose household disinfectants are effective in destroying the virus. Any of these substances are useful in cleaning up mouse excreta and dead mice, and also in disinfecting rodent traps.
Cases of hantavirus pulmonary syndrome contracted in the course of research on these viruses :
• the Morbidity and Mortality Weekly Report for Fri 26 Nov 2004 reported that, in early July 2004, a wildlife sciences graduate student, a man aged 32 years, visited an emergency department (ED) in Blacksburg, Virginia, with complaints of fever, cough, and sore chest since the previous evening. The ED clinician noted possible rodent exposure in the medical history of the patient. Examination revealed a temperature of 102.7 deg F (39.3°C) and an oxygen saturation of 96% (normal). A complete blood count (CBC) revealed a left shift with no bands (granulocytes: 87%) and lymphopenia (lymphocytes: 400/mm³). Radiographic examination indicated faint right-sided pneumonia. In the ED, the graduate student began vomiting and was admitted for intravenous hydration and parenteral antibiotics. He became progressively hypoxic, requiring supplemental oxygen, bilevel positive airway pressure, and eventually intubation with mechanical ventilation. Repeated radiographs revealed bilateral pulmonary edema. According to interviews with his coworkers, the patient had spent the previous month trapping small mammals for study and handling mice (Peromyscus spp.) daily. 2 students and a recent graduate who had worked with the patient reported that none of them had consistently worn gloves while handling rodents or washed their hands after handling rodents or their excreta, even before eating. The students also reported frequent rodent bites on their bare hands. The next day, the patient was hypotensive, requiring intravenous pressor support. He received activated protein C to prevent disseminated intravascular coagulation (DIC). A repeat CBC revealed bands (granulocytes: 20%) and a decreased platelet count (115 000/mm³); urinalysis indicated mild hematuria and proteinuria. Despite aggressive supportive care, the patient's status continued to deteriorate, and he died on the 3rd day of his hospitalization. Differential diagnosis included tularemia, pneumococcal sepsis, and HPS. Serum specimens submitted to ARUP Laboratories (Salt Lake City, Utah) were positive for both IgG and IgM antibodies to hantaviruses; these test results were confirmed by CDC. A spleen biopsy was also positive by immunohistochemistry for hantavirus antigens. A serum sample was positive for hantavirus RNA by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Sequencing of the amplified nucleic acid identified the virus as Monongahela hantavirus. The circumstances of the exposure of the 2 research workers at the university of Colorado remains to be explained, but they appeared to be aware of the hazards and adequately equipped. Further information is awaited
• 2 University of Colorado (UC) researchers from Boulder County, a 24 years old man and a 22 year old woman, who had regular contact with rodents, were diagnosed on 15 Jun and 18 Jul 2005, respectively
It is considered by CDC as a category C biological weapon.
• Hantaan virus
Epidemiology : Asia
Transmission : reservoir : Apodemus agrarius
• Sangassou virus (SANGV), in an African wood mouse (Hylomyscus simus) collected in Guinea is the 1st indigenous African hantavirus
• Seoul virus
Epidemiology : northeastern Asia, and in a milder form in the former Soviet Union, Eastern Europe, Scandinavia, and the southwestern United States.
Transmission : invasion of human dwellings by field and forest rodents (Rattus norvegicus and Rattus rattus) with the onset of colder weather => indirect infection of humans occurs by inhalation of rodent detritus and rarely faecal contamination of food
=> both the abovementioned viruses cause hemorrhagic fever with renal syndrome (HFRS) / epidemic Far East or Hantaan-Korean hantavirus hemorrhagic fever / Korin or Songo fever / Korean hemorrhagic nephrosonephritis : incubation ranges from 9-35 days. Severity of the illness varies, mild or subclinical infections common. More severe cases are characterized by a febrile stage lasting 3-5 days with abrupt onset of fever,headache, photophobia, blurred vision, prostration, nausea and vomiting, facial flushing extending to neck and shoulders, conjunctival petechiae, periorbital edema, acute pharyngitis, axillary petechiae, lumbar back pain and CVA tenderness lasting 3-5 days. The illness may gradually resolve after this febrile stage or a systemic arterial hypotension stage may begin as the temperature falls. The hypotensive stage is characterized by decreased blood pressure, tachycardia, and sometimes shock. Proteinuria, thrombocytopenia, leukocytosis, and acute renal failure occur in some cases. Renal function returns as the oliguric phase resolves and the polyuric phase ensues. Electrolyte imbalances and dehydration may occur in the polyuric phase. Disseminated intravascular coagulation may occur relatively early in the course of illness.
Treatment is supportive.
TGNV represents the 2nd hantavirus from Africa and the 2nd in the world in a shrew (isolated from Crocidura theresae collected in the grassland savannah around the village
Tanganya . However, it does seem likely that Seoul hantavirus is also present in Africa, since it is widely disseminated around the world with the inadvertent transport of infected rats (Rattus spp.) in maritime shipping. One hopes that these researchers will isolate and sequence all of Tan826 virus to permit a complete molecular comparison with the other hantaviruses, and as a candidate for in vivo studies of pathogenesis.  Its low sequence similarity to other hantaviruses should make this virus serologically distinct from other hantaviruses, as shown for TPMV. Therefore, human infections by TGNV might be missed when using antibody detection assays based on antigens from conventional hantaviruses^ref
Thottapalayam virus (TPMV) is the only hantavirus so far isolated from a non-rodent, hence its peculiar place on the genotypic tree of hantaviruses. It was isolated from the spleen of a house shrew (Suncus murinus) in July 1964 (i.e. long before all other known hantaviruses) in Vellore, Southern India. Subsequently there have been no other reports of hantavirus infections in India : it is the only hantavirus isolated in India so far. Not known to have any association with human disease. From 1998 on, we studied the presence of hantavirus-specific IgG and IgM antibodies by means of rNP ELISA for Puumala virus (PUUV) and SIA (strip immunoblot assay) with recombinant PUUV and Seoul virus (SEOV) antigens (B. Hjelle, New Mexico), in Indian sera of cases, suspected for leptospirosis. These sera were kindly forwarded to us by Prof. M Muthusethupathi from the Government General Hospital in Chennai, India, and from Dr G. Nainan from the Medical Trust Hospital, Cochin, India, thanks to the services of Prof. W. Terpstra and Dr. R. Hartskeerl of the Tropical Institute of Biomedical Research, Amsterdam, The Netherlands. However, all were seronegative for leptospirosis in MAT testing in India, and negative in our hands with a specific and probably more sensitive Patoc-IgG & IgM ELISA test. The 1st serological evidence we found of SEOV-like and/or PUVV-like antibodies in these Indian sera was presented as an oral presentation at the 48th Annual Meeting of the American Society of Tropical Medicine and Hygiene (ASTMH), end 1999, in Washington DC, USA^ref.: Clement J, Hinrichsen S, Crescente J, Bigaignon G, Yersin C, Muthusethupathi M, Nainan G, Terpstra W, Hartskeerl R, Lundkvist A, Van Ranst M. Title: Hantavirus-induced hemorrhagic fever with renal syndrome (HFRS) has to be considered in the differential diagnosis of leptospirosis-suspected cases in the New and the Old World. Am J Trop Med Hyg 1999; 61: 316-17. As presented one year later at the 38th Annual meeting of the Infectious Diseases Society of America (IDSA), in New Orleans, USA, 7-10 Sep 2000, no clinical cases of hantavirus infection had been reported at that point from India. In a prospective study in the Chennai and Cochin areas in Southern India, leptospirosis-suspected but Patoc ELISA-IgM negative cases were investigated. Dengue infection was likewise serologically excluded. IgG & IgM SIA testing with recombinant PUUV and SEOV antigens was first performed. We found 7/60 (12%) positives for SEOV, i.e. showing a higher band intensity for SEOV than for PUUV, and 3/60 (5%) PUUV-positives. All IgG SIA-positive cases, except 1 SEOV, were also IgM SIA-positive, thus confirming a recent hantavirus infection in at least 9 Indian cases presenting as "leptospirosis."  2 cases were fatal: one Chennai patient (male, 72 y) developed fever, confusion, acute renal failure (ARF), jaundice, and low platelets (100 000/mm³), and died after 1 day of peritoneal dialysis. In this case, the PUUV IgG & IgM SIA-results were further confirmed by a positive ELISA IgG (but not IgM) result for PUUV. The 2nd fatal case was a Cochin female patient (64 y), who presented with fever, myalgiae, dyspnea and abdominal pain. She developed jaundice, very low platelets (7000/mm³), disseminated intravascular coagulation (DIC), and dialysis-dependent ARF. An adult respiratory distress syndrome (ARDS) picture with extreme hypoxia prompted mechanical ventilation. The patient died in refractory shock on hospital day 7. SIA IgG & IgM was clearly positive for PUUV-bands, and PUUV IgM was likewise positive in ELISA, thus confirming for the 1st time and with 2 different tests a recent and fatal hantaviral infection in an Indian patient. These preliminary results were published as an abstract in: Clement J., Muthusethupathi M., Nainan G., Van Ranst M. First fatal cases of hantavirus nephropathy in India. Clin Inf Dis 2000; 31: 315. The rat-transmitted SEOV serotype is cosmopolitan, with a documented presence also in India. SEOV can induce thrombocytopenia with concomitant kidney and liver involvement, thus perfectly mimicking leptospirosis. The clinical picture is most often of intermediate severity. Although we found evidence of a SEOV-like infection in 12 percent of the Indian "leptospirosis-like" cases,the more severe cases were suggestive rather of a PUUV-like infection, which was surprising. Indeed, whereas in Europe and Russia, PUUV-infections are spread by red bank voles, this rodent and consequently also the virus carried by bank voles are absent from India. We therefore believe that our positive PUUV-results may be merely cross-reactions with TPMV or yet another unknown hantavirus strain in India. In this hypothesis, the low yield in our screening for hantaviruses in India may be explained by the fact that we were using only or in part cross-reacting antigens. From a clinical point of view, it is also unlikely that the severe hospital courses as depicted above could be attributed to a true PUVV infection, whiih is mostly rather mild. In fact, the fatal outcome of the 64-year-old Cochin case with ARF, DIC, ARDS, and refractory shock leading to death one week after admission is highly reminiscent of the severe South American forms of the so-called "hantavirus (cardio-)pulmonary syndrome" or HPS.

• Puumala virus (PUUV)
Epidemiology : human infections typically occur in late autumn or early winter, when the bank voles often invade human dwellings. Consequently, higher than normal numbers of human cases in spring/early summer may indicate a slow decline from a vole peak in autumn 2003, or, a present increase in rodent densities
• Scandinavia (average incidence in Finland is 19/100,000) : about 5% of Finns are seropositive to PUUV. NE is a notifiable disease in Finland. According to national statistics, a drastic change in the human epidemiology has been seen recently. Since the late 1980s until the late 1990s, there were around 1000 (800-1100) human cases annually in Finland, and the yearly variation was not large at the national scale. However, a change took place in 1999, when a record 2305 cases was reached; in 2002, a new record of 2603; and in 2005, 2524 human cases were diagnosed. In addition, the numbers of human cases have been higher than earlier in the between-peak years. The Finnish population is 5.2 million, and 2600 cases means an incidence of 50 / 100 000 in the peak years. For comparison, the same incidence rate would cause nearly 150 000 human cases in the U.S. Fortunately, European NE is a much milder disease than HPS [hantavirus pulmonary syndrome associated predominantly with Sin Nombre virus - Mod.CP] in the Americas, with a case fatality rate < 0.1% in Finland vs. > 30% in the U.S. There are 2 clear trends in the Finnish data. The long-term increasing trend is apparently based on better awareness and diagnostics of the disease. The increasing trend is also clear in local data sets and in between-peak years. However, the most important feature is that the human epidemiology has changed from a rather stable national multi-annual pattern to a strongly cyclic one. The change in NE dynamics is obviously due to the change in the geographic synchrony of vole fluctuations in Finland. In the southern half on Finland, where most people live and most human NE data come from, a vole cycle usually lasts for 3 years, though 4-year cycles are also known. Vole cycles are monitored by the Finnish Forest Research Institute, e.g. to predict the damage risk by rodents in forestry plantations. From the 1970s until the late 1990s, the geographic coverage of a vole peak was not as extensive as it is presently. For example, earlier, a vole peak occurred simultaneously in western and south-central Finland, and a year later in southeastern Finland. In the late 1990s, a change in geographic synchrony took place, and since then, the vole peak has occurred in the same year through most of the southern half of Finland from the western coast to the eastern border. As a result, the number of human cases that earlier were dispersed over 2 or 3 years in geographically different areas now occur in the same year in the whole area. The reason for this geographic change in the synchrony of vole cycles is not well known, but changes like this have taken place earlier and may therefore not be related to any present sudden environmental change. The bank vole densities were very high in Finland in autumn 2005, higher than in 2002, and seroprevalence in bank voles was commonly 20-40% (and based on our ongoing studies, most seropositive voles have viral RNA). Therefore, we expected a new record in human NE numbers in 2005. However, the numbers remained at the same level as n 2002. This might have been because the autumn was exceptionally warm and the autumnal movements of bank voles to human settlements were probably delayed. Consequently, also the seasonal peak in human NE incidence was delayed from late autumn to mid-winter, and over to early 2006. Bank vole numbers were also high on coastal regions in southern and southwestern Finland, resulting in 4-5 times more NE cases than normally in these regions, where NE usually is not common
• Russia (Bashkortostan (earlier Bashkiriya), its capital Ufa, and the surrounding area : large focus which extends from Samara, on the river Volga, and surrounding areas east to Bashkortostan and south to Uralsk on the Kazakhstan side). Over the past few years, reports of outbreaks of HFRS have been reported regularly from Tatarstan and other regions along the Volga River, where Puumala virus is the likely etiologic agent : bank vole populations in these regions fluctuate naturally, and the peaks seem to follow a 3-year pattern. A huge epidemic occurred along the Volga River with thousands of human cases in the late 1990s. On average, the number of HFRS cases recorded in the Khabarovsk region annually ranges from 20 to 100 cases. However, in 2004 the Khabarovsk region was not included in the list of high risk regions for HFRS infection. The Khabarovsk region is located in the far eastern part of Russia, bounded in the east by the Sea of Okhotsk and the Sea of Japan. In the south, the Khabarovsk region borders the Heilongjiang province of China. In the southwest and west, it borders the Amur region; in the northwest and north, the Republic of Sakha; and in the northeast, the Magadan region. The mountain ranges of Sykgote-Alin, Jzhugzhur, and Suntar-Khayat occupy the greater part of the territory. The capital is Khabarovsk (Lat 48o 30'N; Long 135o 5'60"E), with 58 3000 inhabitants (2003 census)
From 1 Jan to 15 Jun 2005, 120 cases were reported in Belgium and 115 cases in France. In Germany, 258 laboratory-confirmed hantavirus cases were reported between 1 Jan and 30 Jun 2005 and, in contrast to previous annual trends, the increase in cases has occurred earlier in 2005. The total numbers of cases for 2003 and 2004 were, respectively, 122 and 47 in Belgium, 128 and 55 in France. In Germany the numbers of reported cases for 2003 and 2004 from 1 Jan to 30 Jun were 72 and 64, respectively. In 2005, most cases have been in men; the male:female sex ratio was 3.0 in Belgium, 3.4 in France, and 2.5 in Germany. Their mean age was around 41 years in all 3 countries: 43 (range: 11 to 82 years) in Belgium, 43 (range: 16 to 83 years) in France and 41 (range: 5 to 75 years) in Germany. In Germany, most infections were caused by the hantavirus species Puumala virus (n=212, 82%), 5 infections (2%) were caused by Dobrava virus and for 41 cases the causative virus was not specified (16%).
• Belgium : the area most affected in this outbreak is Luxembourg province, where there have been 34 cases, an incidence of 2.0 per 100 000 inhabitants, followed by Liege province (27 cases, 2.6/100 000) and the Namur province (25 cases, 5.5/100 000). A large number of cases in Liege province was observed in 2003. In Belgium, hantavirus epidemics are characterised by a minor spring peak and a major summer peak, and so a further increase in the registered number of cases is anticipated for 2005. According to local health professionals, part of this increase is due to a greater awareness among health professionals and a higher recourse to hantavirus testing. Risk factors for Belgian cases are not yet available. Since 1980. over 1200 cases have been diagnosed in Belgium, and outbreaks of hantavirus infections in humans have been described in 1985, 1990, 1991, 1993, 1996, 1999, 2001 and 2003, with most cases having onset in summer. Known endemic areas are the provinces of Hainaut, Namur and Luxembourg. In Belgium, the national reference laboratory for hantavirus infections and the IPH sentinel laboratory network report data to the Scientific Institute of Public Health (IPH). Until 1999 (with epidemics in 1990 with 62 cases, 1993 with 174 cases, 1996 with 224 cases, 1999 with 124 cases) a 3-year cycle in increased hantavirus infection activity could be observed, from this year on and up until 2005 a 2-year cycle occurred (epidemics in 2001 with 110 cases, 2003 with 122 cases and 2005 with 372 cases). Surprisingly, 2006 resulted in 160 cases and was the 1st epidemic year with no preceding non-epidemic year (Heyman, P., Van Mele, R., De Jaegere, F., Klingstrom, J., Vandenvelde, C., Lundkvist, A., Rozenfeld, F., and Zizi, M. Distribution of hantavirus foci in Belgium. Acta Trop. 2002;84:183-188; Heyman, P., Vervoort, T., Colson, P., Chu, Y. K., Avsic-Zupanc, T., and Lundkvist, A. A major outbreak of hantavirus infection in Belgium in 1995 and 1996. Epidemiol.Infect. 1999;122:447-453; Heyman, P., Vervoort, T., Escutenaire, S., Degrave, E., Konings, J., Vandenvelde, C., and Verhagen, R. Incidence of hantavirus infections in Belgium. Virus Res. 2001;77:71-80; Mailles, A., Sin, M. A., Ducoffre, G., Heyman, P., Koch, J., and Zeller, H. Larger than usual increase in cases of hantavirus infections in Belgium, France and Germany, June 2005. Euro.Surveill. 2005;10:E050721-)
• France : most of the 2005 cases in France are in the Ardennes (40 cases, 13.8/100 000) and the Aisne Administrative Departements (18 cases, 6.9/100 000) in northern France, bordering on Belgium. The Departement of Jura bordering on Switzerland is also an epidemic area, with 13 cases to 15 Jun 2005 (5.2/100 000). Since 1980, over 1000 cases of hantavirus infection have been diagnosed in France. Hantavirus outbreaks have been described in 1985, 1990, 1991, 1993, 1996, 1999, and 2003, with most cases having onset in summer. The known endemic areas in previous years have been northeastern France, along the Belgian and German borders (in the Administrative Departements of Ardennes, Aisne, Nord and the administrative regions of Lorraine, Picardie and Franche-Comte). Clusters of hantavirus infections have rarely been reported in the Jura before 2005. In France, the national reference laboratory for hantavirus infections is in charge of surveillance of human infections.
• Germany : the increase of hantavirus infections in Germany between 1 Jan and 30 Jun 2005 has also been seen in federal states such as Nordrhein-Westfalen, Niedersachsen and Hessen, that have not had high hantavirus prevalence in previous years. The federal states most affected are Nordrhein-Westfalen (92 cases, 0.5/100 000), Niedersachsen (51 cases, 0.6/100 000), Baden-Wuerttemberg (46 cases, 0.4/100 000), Hessen (23 cases, 0.4/100 000) and Bayern (23 cases, 0.2/100 000). In Germany, the average incidence for hantavirus infections over the time period 2001-2004 was 0.25/100 000. An increase in hantavirus infections was observed in 2002 and 2004. In both years the increase was due to outbreaks in a known endemic area of Baden-Wuerttemberg, and an outbreak of 38 cases also occurred in Niederbayern in 2004. In Germany, the known regions with higher prevalence of human hantavirus infections are Schwaebische Alb in Baden-Wuerttemberg and parts of Unterfranken in Bayern (Bavaria). Hantavirus infection became a notifiable disease in Germany with the introduction of the Infektionsschutzgesetz (the Protection against Infection Act) in 2001. Reports of laboratory confirmed Hantavirus infections are transmitted to the Robert Koch-Institut (RKI) based on a case definition^ref. In many forest and agricultural regions of Belgium, France and Germany, a significant increase in the population density of rodents, especially voles, has been observed since the autumn of 2004, with no sign of this increase abating.
Control measures and recommendations : an alert was sent out from France through the European Early Warning and Response System (EWRS) on 21 Jun 2005, and subsequent messages were sent through this system from Germany (22 June) and Belgium (5 July). General recommendations for avoiding hantavirus infection include preventing rodent access to houses or buildings. Any factor that could attract rodents inside, such as keeping uncovered food, should be avoided. When cleaning a previously unoccupied building where rodents may have settled, soil and surfaces should be sprayed with a disinfectant before dust is removed. People living in endemic areas should be informed about the risk factors and clinical symptoms of the disease, and advised to seek medical attention and report their risk exposure if they develop symptoms consistent with haemorrhagic fever with renal syndrome (HFRS). A case control study including Belgian and French cases identified the main risk factors as living < 50 m from a forest and seeing rodents in or around the home, digging, spending long periods in the forest and being in contact with wood or disturbed earth or dust^ref. Information has been released to the general public in Liege province in Belgium, and general information is available on the website of the Scientific Institute of Public Health (IPH), Brussels and the national reference laboratory's website. An update of the situation on 24 Jun 2005 is also available on the IPH website^ref. Printed versions of the leaflet have been widely distributed and more copies can be obtained from the IPH. In France, information about the disease and recommendations for avoiding infection have been issued in the national media to alert the resident population in affected areas and tourists. A leaflet is being printed by the Ministry of Health describing the clinical features of hantavirus infection and general recommendations protecting homes from rodents and avoiding infection when working or spending leisure time outdoors, and this will be soon available in camping sites, leisure centres and tourist information offices. The InVS [Institut de veille sanitaire] has published a press release^ref and more information is available at the websites of the Ministry of Health and the Institut Pasteur. In Germany, a further increase in human cases is expected during the following months. Health care professionals around Germany are increasingly aware of the disease, and guidelines for preventing hantavirus infection are available on the RKI website^ref. In collaboration with the federal and local health departments, the RKI is conducting a nationwide case control study to identify more specific risk factors for human hantavirus infections in Germany^ref. There are plans to trap rodents in affected areas to test for hantavirus infection. The larger than usual increase in hantavirus infections in France, Belgium and Germany in 2005 that was recently reported^ref is also being observed in Luxembourg, which is surrounded by these 3 countries. Since March 2005, 14 cases of Puumala virus infection have been laboratory-confirmed in Luxembourg, compared with 2 cases in 2003 and no cases in 2004. 2 of these patients lived in towns on the borders with Belgium and France. The other 12 patients living in Luxembourg are clustered in the rural region of Mullerthal and surrounding areas in the east of the country, which suggests that the outbreak in Luxembourg is quite localised. The Mullerthal is an area characterised by beech forests and sandstone formations. The mean age of patients is 41 years (range 21 to 70), similar to that observed in the neighbouring countries^ref. The male-to-female ratio is 1.9. Most cases so far confirmed occurred in June and it is not clear whether the incidence has already peaked. Hantaviruses are carried by bank voles and their population size is known to vary according to the availability of food. 2004 was a 'mast year'' [the fruit of beech and similar broad-leaved trees is known as 'mast'] in Luxembourg for beech trees, a common broadleaf tree species. This means that there were unusually large seed crops, and is the most likely reason for an increase of the bank vole population this year. In the past, the peak of human hantavirus cases in the Ardennes region (which encompasses parts of northeastern France, Belgium, Luxembourg and Germany) have tended to occur in spring and summer, unlike the cases in northern Europe which tended to peak in autumn and early winter^ref. Given the direct epidemiological link between bank voles and hantavirus, it is quite likely that a higher incidence of human hantavirus infections is to be expected in other areas belonging to the western European broadleaf forests, where beech mast years may also have occurred in 2004. Western European broadleaf forests are found in Austria, Belgium, the Czech Republic, France, Germany, Luxembourg and Switzerland^ref. In July 2005, all physicians and the general public in Luxembourg were informed by the Health Directorate's Health Inspection about the increased risks of hantavirus infections, and recommendations for avoiding infection were published^ref
Susceptibility : HLA-B8-DR3 is a more important risk factor for severe infection than the TNF-a(-308) G/A polymorphism.
Transmission : reservoir : Clethrionomys glareolus. HFRS cases are usually coincident with invasion of human dwellings by field and forest rodents with the onset of colder weather. Indirect infection of humans occurs by inhalation of rodent detritus, although some outbreaks have been related to fecal contamination of food supplies.
=> epidemic nephropathy / nephropathia epidemica, a milder form of HFRS than that caused by Hantaan virus : 10-25 days incubation => fever, oliguria => polyuria and hydroelectrolytical disequilibrium after recovery. Also infects intestine^ref
Prognosis : lethality is < 0.1%
Prevention : wear gloves and a dust mask when cleaning a rodent-infested area or a shed or cabin that has been closed up. Soak mouse nests and droppings with a solution that is one cup bleach to 10 cups water. Don't stir up any dust; use mops or rags soaked in the bleach solution.
Epidemiology :
• Nepal : an overall seropositivity rate of 8.7% of 322 specimens from patients attending outpatient clinics at the Tribhuvan University Teaching Hospital in Kathmandu. Of note, a higher positivity rate of 12% was seen in those living outside of the Kathmandu valley (5.1%), suggesting hantavirus infection was more prevalent in rural areas^ref.
• Russia : 52 different species of mammals have been shown to serve as hosts of hantaviruses (EA Tkachenko et al. [1998] HFRS in Eurasia: Russia and the republics of the former USSR, in HW Lee, C Calisher, C Schmaljohn [eds.] Manual of hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Asan Inst. for Life Sciences, Seoul, Republic of Korea, pp:49-57). 3 of these belong to the genus Clethrionomys: Clethrionomys glareolus (bank vole), Clethrionomys rufocanus, and Clethrionomys rutilus. HFRS is endemic in the Republic of Tatarstan. Public health authorities in Russia reported in April 2005 that the incidence of rodentborne HFRS nationwide during 2004 was 66.4% higher than the 2003 level, with a 180% increase reported among children under the age of 14. These new national statistics followed previous announcements of a 13-fold increase in the incidence of HFRS in Nizhnii Novgorod and a 21-fold increase in Sverdlovsk during 2004. 10 244 cases of HFRS -- including 377 cases in children under age 14 -- were reported from Russia in 2004. The national rate of HFRS incidence for 2004 was cited as 7.1 per 100 000 inhabitants, whereas in 2003 it was 4.3. The general incidence rose by 66.4%, including a 2.8-fold rise among children under age 14. Rates of HFRS transmission in Sverdlovsk Oblast were 21 times higher in 2004 than during 2003, and > 8 times higher than the running average for the region over the past several years. Rates of infection for tularemia in Russia as a whole were reported to be 3 times higher during the 1st 9 months of 2004 than they were in 2003^ref. The reported massive increases in animalborne diseases are attributable to a combination of breakdowns in vaccination and rodent control programs at the local and provincial levels due to reduced government funding levels and massive increases in population densities of disease-carrying rodents. Officials attributed an observed 6-fold increase in the number of fox-transmitted rabies incidents among humans in Sverdlovsk Oblast during January 2005 over 2004 levels to unusually high survivorship rates of young foxes permitted by recent population explosions among their usual prey species: rodents, rabbits, and other small mammals. The highest number of HFRS cases in 2004 was recorded in the Privolzhskiy Federal District -- 28.2 per 100 000 inhabitants, 4 times the average for Russia as a whole. In 2004 in Mariy El Republic HFRS morbidity was 53.2 per 100 000 inhabitants^ref : in total 387 cases of HFRS, 4 of which had a fatal outcome, were recorded in Mariy El in 2004
• Canada : the 1st documented case of HPS occurred in Alberta in 1989. Although it is possible that several species/genotypes of hantaviruses are present in Canada, only Sin Nombre virus and Prospect Hill virus have actually been documented by serological and phylogenetic characterization^ref to be associated with rodents in this country. Hantavirus-infected deer mice have been found in every province except Prince Edward Island and Nova Scotia. Deer mice infected with viral strains closely related to New York virus have been found in eastern Canada (Newfoundland, New Brunswick, Quebec and Ontario). Mice infected with strains related to Sin Nombre virus and have been found west of Ontario. Consequently the hantavirus responsible for the death of the teenager in British Columbia is likely to be Sin Nombre virus. Currently, there are 62 documented HPS cases in Canada. All but one of these cases were identified in the provinces of Manitoba, Saskatchewan, Alberta, and British Columbia. The other case was identified in the province of Quebec, the only patient ever identified east of Manitoba (despite the fact that we have found infected deer mice from British Columbia to Newfoundland). All cases appear to have been associated with Sin Nombre virus. The other hantavirus we have in Canada is Prospect Hill virus; but to my knowledge, there is no evidence to indicate that it is a human pathogen. Of interest, we have also documented an imported case from Argentina (involving a Saskatchewan resident who was visiting a site within the Buenos Aires district). Blood clots from this individual ere PCR positive for an Andes-like virus.
• Argentina : several hantaviruses have been associated with human infection in Argentina: Andes virus (western Argentina, in the long-tailed pigmy rice rat host, Oligoryzomys longicaudatus), related Andes-like viruses Hu39694 (in central Argentina; rodent host unknown), Lechiguanas (in central Argentina in O. flavescens), Oran (in northwestern Argentina in O. longicaudatus), and Bermejo (western Argentina in O. flavescens) virus
• India : 2 fatal hantavirus cases in India were reported in 2005^ref. Serological tests in the Clement et al. study implicated Puumala virus or a hantavirus antigenically related to it as the etiological agent in these 2 cases.  The only hantavirus previously known to occur in India was Thottapalayam virus, and is not known to be a cause of human disease. Given its ubiquity, Seoul virus is likely present in India as well.
• Nairovirus contains at least 33 species in 7 serogroups. The chief vectors are ticks of the genera Amblyomma and Hyalomma
• Crimean-Congo hemorrhagic fever virus (CCHFV)
• Hazara virus
Epidemiology : first identified in 1944 on the Crimean peninsula in what was then the Soviet Union. The Congo appellation was added in 1969 after the discovery that the same disease had been found in central Africa in 1956. Nowadays found in Crimea, Central Asia (endemic in the border region between the Baluchistan province of Pakistan and Afghanistan and in the southern part of Kazakhstan), Bulgaria, and West, Central, and East Africa.
• Russia : outbreaks have been reported in the Stavropol area at least 15 times since 1999 : the CCHF seasonal epidemic seems to peak around April and May each year. The City of Stavropol (1989 pop. 318 000), is the capital of Stavropol Territory in southern European Russia, on the Stavropol Plateau.  It has machine-tool, wool, leather, grain milling, and food-processing industries. There are natural-gas fields in the area. Founded in 1777 as a Russian fortress, it was an important base for the subsequent Russian conquest of the Caucasus. 41 cases of CCHF were registered in the Stavropol region in 2006
• Iran : 18 confirmed out of 84 suspected cases in 2005
• China : first reported in China in 1964. Cases are reported from the south west region. 260 cases (54 fatal) were reported in Xinjiang (southern desert region) during 1964 to 1995. 10 to 20% of sheep, goats, and cattle in Sichuan are seropositive.
• South Africa : the 1st case was diagnosed in 1981 when the virus was isolated from the blood of a schoolboy who died after being bitten by a tick in the North West Province. This prompted investigations to determine the prevalence of the virus in the country. Results of antibody surveys on sera from humans, livestock and wild vertebrates confirmed that the virus is widespread in South Africa in areas corresponding to the distribution of ticks belonging to the genus Hyalomma. The wide distribution of antibody and its detection in sera which had been stored for several years indicated that the virus had been present for many years and was not a recent introduction^ref
• Turkey : since it first appeared in 2003, 44 people have died from the disease, most of them in the central Anatolia provinces, with case fatality around 5%. Between 1 Jan and 30 Jun 2006, 150 laboratory-confirmed cases including 11 deaths from Tokat, Sivas, Gumushane, Amasya, Yozgat & Corum provinces^ref
Genomics : segmented 3 part genome, ambisense coding capacity.
Transmission :
• bite or crushing of infected ticks (a zooanthroponosis; vector Hyalomma marginatum (transovarial and transstadial transmission))
• contact with live or dead infected mammals or their tissues (tick larvae and nymphs parasitize Aves spp. and small mammals, whereas adult ticks attack larger wild and domestic ruminants like Ovis aries, Capra hircus and Bos taurus). Infection of wild and domestic ruminants results in abundant production of CCHFV. Remarkably, there is no evidence of clinical disease in animals other than humans
• contact with blood, secretions, or fluids from infected humans : consequently nosocomial infection is not uncommon, especially where disease is not recognized and there are no facilities for precise diagnosis. In 2002, a female doctor in hospitals in Rawalpindi contracted CCHFV infection from a patient and died. 2 doctors involved in her treatment also contracted infection; both survived. Previously, in 1974, a physician died in Rawalpindi General Hospital as a result of CCHFV infection contracted from patients.
• iatrogenic transmission
=> many human infections are inapparent
=> Crimean-Congo hemorrhagic fever (CCHF) / Xinjiang hemorrhagic fever : 3-12 days incubation => sudden onset fever and myalgia, headache, dizziness, photophobia, hyperesthesias, chest, back and/or abdominal pain, nausea and vomiting, conjunctivitis, flushing, systemic arterial hypotension, axillary or other petechiae, systemic arterial hypotension, tachycardia, periorbital edema, proteinuria, acute hepatitis, jaundice, hepatomegaly, elevated serum levels of liver enzymes (AST, CPK), leukocytosis, and DIC after several days of infection. Death usually occurs during the second week of illness, preceded by hemorrhages, shock, pulmonary edema and acute renal failure.
Therapy : IV ribavirin, surgical stemming of internal hemorrhage and blood transfusion.
Lethality can be as high as 40% in extreme situations but is normally in the region of 15% (5-50% depending on the availability of modern medical care)
Prevention : there is currently only a mouse brain-derived vaccine, but a much safer one is needed.
• Nairobi sheep disease virus (NSDV) / Ganjam virus
Epidemiology : highly pathogenic for Ovis aries and goats, causes disease in humans, and is widespread throughout East Africa. Ganjam virus has caused disease in goats and humans in India. Due to their occurrence on different continents and association with different ticks, these viruses were considered distinct despite serologic cross-reactivity. Their S RNA genome segments and encoded nucleocapsid proteins were found to be 1590 nucleotides and 482 amino acids in length and differed by only 10 and 3% at nucleotide and amino acid levels, respectively. Genetic and serologic data demonstrate that Ganjam virus is an Asian variant of NSD virus. These viruses were phylogenetically more closely related to Hazara virus than Dugbe virus.
Transmission : tick-borne (Haemaphysalis intermedia)
=> Nairobi sheep disease (NSD)
• Orthobunyavirus [Bunyamwera, town in Uganda where the type species was isolated] : the Bunyamwera supergroup of viruses; a widespread genus of viruses of the family Bunyaviridae, containing at least 161 species in 18 serogroups and 4 unclassified species; human pathogens of this genus cause febrile disease and encephalitis. The usual mode of transmission is by the bite of infected mosquitoes, although a few species are tick-borne. Genetic reassortment among members of the same serogroup within the Orthobunyavirus genus occurs in nature and has led to the emergence of new viruses, only occasionally with increased pathogenicity. They have a trisegmented (large [L], medium [M], and small [S] segments) negative-sense RNA genome. The L RNA segment encodes for the RNA-dependent RNA polymerase, the M segment encodes for the glycoproteins Gn and Gc, and the S segment encodes for the nucleocapsid protein. Many orthobunyaviruses also encode the nonstructural proteins NSm and NSs within the M and S segments, respectively; however, these proteins are not encoded in all orthobunyaviruses described.
  
• Bunyamwera virus
• Batai virus
=> febrile illnes in South-Eastern Asia
• Birao virus
• Bozo virus
• Cache Valley virus (CVV)
Epidemiology : all North America, except the extreme southeastern states and southern Mexico. First isolated from Culiseta inornata mosquitoes collected in Cache Valley, Utah, in 1956 (Karabatsos N, editor. International catalogue of arboviruses, including certain other viruses of vertebrates. San Antonio (TX): American Society of Tropical Medicine and Hygiene; 1985). Previous serosurveys have indicated that humans in some parts of the USA are commonly infected by Bunyamwera serogroup viruses. For example, neutralizing antibody to CVV was found in 12% of 356 persons surveyed in Maryland and Virginia in the 1960s^ref. Such results, however, are often difficult to interpret because of nonrandom sampling, multiple Bunyamwera serogroup members circulating in the same area, inclusion of a limited number of viruses in tests, and serologic cross-reactivity among members of the serogroup.
Transmission : although it has been isolated from >20 different species of culicine or anopheline mosquitoes (Culiseta spp., Anopheles spp., and Aedes spp.), most frequently from Anopheles quadrimaculatus^ref, the principal mosquito vectors are unknown. The vertebrate amplifying hosts of CVV have been little studied, but a high prevalance of neutralizing antibody to this virus is often found in ungulates^ref, including deer, sheep, horses, and cattle^{ref1, ref2, ref3}. The virus has been isolated from a healthy cow and a sick sheep in Texas^ref and from a healthy horse in Michigan^ref. It is teratogenic in sheep^ref. Mutual exclusion with Tensaw virus likely occurs because of cross-protectivity between them
=> only 3 cases of human disease due to Bunyamwera serogroup viruses were previously reported in temperate North America.
• the first was an encephalitis case in Indiana attributed to Tensaw virus in 1964. Unfortunately, because no details about this case or the method of diagnosis were provided, and because the known range of Tensaw virus does not include Indiana, the validity of this report is uncertain.
• the second was a fatal, culture-confirmed case of CVV encephalitis in a young adult in North Carolina in 1995^ref
• meningitis in a a 41-year-old man in October 2003 who recovered^ref
Antibodies cause congenital malformations^ref
Laboratory examinations : viral genomic sequence data and high-titer neutralizing antibody to CVV in the patient's convalescent-phase serum. Few CSF specimens are cultured for arboviruses because relatively few diagnostic laboratories have the expertise to do so and because even in acute, serologically confirmed cases of neuroinvasive arboviral disease, the isolation rate from CSF is generally low. No tests for CVV immunoglobulin M, such as enzyme immunoassay, are available. Tests for neutralizing antibody to this virus require handling live virus under biosafety level 2 containment and thus are only available by special request at CDC (through state health departments) and selected reference laboratories
• Cache Valley–like virus
Epidemiology : isolated from human blood in Central America (Panama ?^ref)

• Caraparu virus
  
  • Apeu virus
  • Bruconha virus
  • Ossa virus
  • Vinces virus
• Fort Sherman virus
=> fever-myalgia syndrome in Central America
• Iaco virus
• Ilesha virus
Epidemiology : isolated from human blood in Africa
• Itaya virus
  

Epidemiology : isolated in 1999 and 2006 from febrile patients in the cities of Iquitos and Yurimaguas in Peru. The geographic distance between the 2 cases suggests that the Itaya virus could be widely distributed throughout the Amazon basin in northeastern Peru^ref

• Lokern virus
• Mboke virus
• Ngari virus, which has been associated with hemorrhagic fever in Kenya and Somalia. This virus is comprised of the S and L segments of Bunyamwera virus and the M segment of Batai virus. On the basis of genetic and antigenic analyses, the authors previously reported that Jatobal virus (JAT), a member of the Simbu serogroup, is a reassortant virus that contains the S segment of ORO virus and the M and L segments of a still unrecognized Simbu serogroup virus.
  
• Northway virus
• Playas virus
• Potosi virus
• Shokwe virus
Epidemiology : isolated from human blood in Africa
• Tensaw virus (TEN)
Epidemiology : southeastern United States
Transmission : isolated from Anopheles spp. and Aedes spp.; mutual exclusion with Cache Valley virus likely occurs because of cross-protectivity between them
• Tlacotalpan virus
• Xingu virus
Epidemiology : isolated from human blood in South America
• Ngari virus
Genomics : L and S segments show high sequence identity with those of Bunyamwera virus
• Garissa virus
Epidemiology : outbreak in East Africa (Kenya and Somalia) in 1997 and 1998
Genomics : 3 genomic RNA segments. It a genetic reassortant virus with S and L segments derived from Bunyamwera virus and an M segment from Ngari virus^ref
Symptoms & signs : hemorrhagic fever
Epidemiology : Uganda
Transmission : Aedes spp.
=> infection is usually asymptomatic, but a mild febrile illness may result
• Calovo virus
=> febrile illness in Europe
• Germiston virus

Epidemiology : isolated from human blood in Africa
• Guaroa virus
=> isolated in Colombia from the blood of patients with a febrile disease.
• Lumbo virus
• Maguari virus
• Northway virus
=> fever and headache
Main Drain virus
Wyeomyia virus
• Anhembi virus
• BeAr328208 virus
• Macaua virus
• Sororoca virus
• Taiassui virus
Epidemiology : Central and South America and Trinidad
Transmission : originally isolated from the mosquito Wyeomyia melanocephala
=> febrile illness
• Bwamba virus group
• Bwamba virus
Transmission : mosquito-borne, originally isolated in Uganda but prevalent in eastern, central, western, and parts of southern Africa
=> Bwamba fever : a mild fever
• Pongola virus
Transmission : mosquito-borne virus of the Bwamba serogroup of the genus Bunyavirus, serologically, occurring in central and southern Africa. Natural hosts are donkeys, Equus caballus, and monkeys; human infection is asymptomatic
• California encephalitis virus group
• California encephalitis virus
Epidemiology : primarily affects children in western United States and Canada
Transmission : a zooanthroponosis; reservoir : squirrels and other Rodentia; vectors : Aedes atlanticus, Aedes infirmatus, Culex tarsalis, Aedes melanimon
After 4-20 days incubation :
=> commonly benign aseptic encephalitis
=> rarely acute California encephalitis
• Inkoo virus
• Jamestown Canyon virus
Epidemiology : Clinton County in New York state, USA
Transmission : mosquito-borne; mammals, such as mice, chipmunks, and whitetail deer, may be carriers
After 5-15 days incubation : fever, chills, nausea, vomiting, headaches, and abdominal pain
=> occasionally causes encephalitis^{ref1, ref2}
• La Crosse virus
Epidemiology : named after La Crosse, Wisconsin, the place where it was first described in 1963. La Crosse virus is the leading cause of pediatric arboviral encephalitis in the USA. According to the CDC, there are about 70 human cases annually. La Crosse virus is present in the USA to the east of the Mississippi river, and serological studies indicate that human infections occur throughout the range of the mosquito vector whose density peaks between June and September. Human cases of encephalitis are correspondingly seasonal. La Crosse virus is responsible for the majority of human cases of encephalitis caused by California encephalitis viruses. La Crosse encephalitis occurs predominantly in the mid-western states, and children are at greatest risk
Transmission : maintained in nature by infection of alternate hosts -- mosquitoes and small mammals. Its main vectors are Ochlerotatus triseriatus, a mosquito of woodlands, and small mammals such as chipmunks and squirrels. These small mammals may become sufficiently viremic to infect hematophagous mosquitoes
=> La Crosse acute encephalitis. The incubation period is about one week, followed by a non-specific febrile period and an acute encephalitis which may last up to 10 days. Although there may be persistent disabilities in a minority of cases, fatalities are rare
Laboratory examinations : at least one person with La Crosse virus infection (confirmed in other ways) had IgM antibody to the virus for at least 104 days after onset of illness^ref. Therefore, the presence of IgM antibody to this virus in a single serum cannot be used to make a confirmed diagnosis. Provisional serodiagnosis of La Crosse virus infections may be made if IgM antibody is detected in patient's blood, but paired acute- and convalescent-phase samples must be obtained before it is possible to make a confirmed serodiagnosis  If acute serology is negative, it is ideal to obtain convalescent titers sic as well
Web resources : La Crosse Maps - Human - USA
• Lumbo virus
Epidemiology : Africa
• snowshoe hare virus (SHV / SSHV)
• Tahyna virus
Epidemiology : first isolated in the Slovakian village of Tahyna in 1958.
• Austria : isolated from mosquitoes (Aedes caspius) on the eastern shore of Lake Neusied. Antibodies against Tahyna virus have been documented among wild and domestic mammals in the eastern Neusiedlersee area.
• Croatia : seropositivity toward Tahyna virus is found among wild bears (Ursus arctos).
• Czech Republic : evidence for Tahyna virus infection has been demonstrated in the Czech Republic including midges and humans in West Bohemia; and in humans and cormorants in Moravia. Following floods in 2000, 16% of persons in the Melnik region were found to be seropositive toward Tahyna virus. Tahnya virus was isolated from mosquitoes (Ae. vexans and Ae. cinereus) in Moravia in 1997; and again (Ae. vexans) in 1999. Seroprevalence toward Tahyna (Batai) virus has been demonstrated in wild animals.
• France : identified in mosquitoes (Culex modestus) in France. During 1975 to 1979, antibody toward Tahyna virus was found in 31% of humans and 9 percent of horses in the region of Camargue.
• Germany : isolated from domestic animals in the former East Germany; and from Aedes vexans in Upper Rhine area near Germersheim (Isle Grun).
• Italy : seropositivity toward Tahyna virus has been demonstrated in small mammals. Tahyna virus has been isolated from Aedes mosquitoes in Northern Italy (Gorizia Province).
• Macedonia : seropositivity toward Tahyna virus is found among wild bears (Ursus arctos).
• Morocco [of interest by contiguity to Spain] : 21% of small mammals surveyed in 1979 were found to be seropositive
• toward Tahyna virus.
• Norway : viruses related or identical to Tahnya virus have been isolated from mosquito species (Aedes sticticus, Ae. diantaeus andAe. hexodontus) collected from Oyern, Trandum and Masi.
• Poland : antibodies to Tahnya virus have been detected in house sparrows (Passer domesticus) and tree sparrows (P. montanus) in central Poland.
• Romania : seropositivity toward Tahyna virus has been demonstrated in humans.
• Russian Federation : Tahyna, Inkoo, and other variants are present. Rates are highest in summer and in persons below age 30. Over 100 human infections were documented during 1985 to 1990. Highest risk exists in western Siberia (Ryazan region, Sverdlovsk). Seropositivity is documented among humans in Irkutsk. 40% of healthy blood donors, and 4 to 14% of febrile patients with neurological signs in the Ryazan region were seropositive to Tahyna or Inkoo viruses in 1991. Mosquito infection rates (1983 to 1991) vary: 0.009% (tundra), 0.012% (forest-tundra), 0.01% (northern taiga), 0.02% (central taiga), 0.017 per cent (southern taiga), 0.026% (forest steppe), 0.097% (steppe). Vectors include Aedes communis, A. excurians,A. cantans, A. flavescens, A. ciprius, A. punctor, A. vexans, A. (Ochlerotatus) cataphylla, A. nigripes, A. hexodontus, Oclerotatus impiger (Sakhalin Island) and O. communis (Kalinin region).
• Serbia and Montenegro : human infection by Tahyna virus has been reported. Seropositivity toward this agent is found among wild animals.
• Slovakia : seropositive birds and sheep are reported. Natural infection of mosquitoes (Aedes vexans) and midges (Ceratopogonidae) has been identified.
• Spain : seropositivity toward Tahyna virus has been demonstrated in small mammals.
• Tajikistan : Tahyna virus has been identified in the blood of febrile patients, and in mosquitoes collected in Dushanbe.
Transmission : the principal vector is Aedes vexans; with additional transmission by Ae. cantans, Ae. caspius, Ae. cinereus, Anopheles hyrcanus, An.maculipennis, Culex modestus, Cx. pipiens and Culiseta annulata; rabbits and birds^ref
=> fever, sometimes associated with acute pharyngitis, lung symptoms and aseptical meningitis.
• Trivittatus virus
• Guama virus
Epidemiology : isolated in the region of Belem, Brazil, from foresters
Symptoms & signs : hyperthermia, headache, muscular and articular pains, and occasionally nausea and vertigo.
• Catu virus : a species closely related to Guama virus
Epidemiology : isolated from a Brazilian patient
Symptoms & signs : a febrile illness.
• Germisten virus : an arbovirus that causes a mild febrile disease in South Africa
• Kairi virus
• Kairi virus
• Mapputta virus group
• Gan Gan virus
• Shuni virus (SHUV)

Epidemiology : was first isolated in Nigeria in 1966 during surveys of livestock, Culicoides midges, and mosquitoes, SHUV also once was isolated from a febrile child^{ref1, ref2}. SHUV recently was identified as a previously undetected cause of neurologic disease in horses in southern Africa^ref and veterinarians in South Africa^ref and is thus of interest in comparison to WNV.

• Simbu virus Group
• Aino virus
• Akabane virus
• Sabo virus
• Yaba-7 virus
• Jatobal virus
• Oropouche virus (OROV)
Epidemiology : originally reported in Trinidad in 1955, when the prototype virus strain was isolated from the blood of a febrile patient and from a pool of Coquillettidia venezuelensis mosquitoes^ref. In Brazil, OROV was initially described in 1960, when it was isolated from a sloth (Bradypus tridactylus) captured near a forest area during the construction of the Belém-Brasilia highway, and from a pool of Ochlerotatus serratus mosquitoes captured nearby (Pinheiro FP, Pinheiro M, Bensabath G, Causey OR, Shope RE. Epidemia de vírus Oropouche em Belém. Revista do Servico Especial de Saúde Pública. 1962;12:15–23)^ref. > 500,000 persons have been infected with OROV, which makes this virus a public health threat in tropical and subtropical areas of Central and South America (Pinheiro FP, Travassos da Rosa APA, Vasconcelos PFC. Oropouche fever. In: Feigin RD, editor. Textbook of pediatric infectious diseases. Philadelphia: W.B. Saunders Co.; 2004. p. 2418–23). Explosive Oropouche fever epidemics have been reported in all of the following areas in Brazil: Maranhão, Tocantins, Amazonas, Acre, Pará, and Rondônia States. Such epidemics have also been reported in Iquitos and Madre de Dios, Peru; and in Bejuco, Panama (Pinheiro FP, Travassos da Rosa APA, Vasconcelos PFC. Oropouche fever. In: Feigin RD, editor. Textbook of pediatric infectious diseases. Philadelphia: W.B. Saunders Co.; 2004. p. 2418–23). Molecular studies^ref recognized 3 genotypes and suggested the distribution for OROV in South and Central America. The authors showed that in Brazil, genotype I, the most widespread in the country, and genotype II, found in Rondônia (a bordering state with Peru), and also in Para state (M.R.T. Nunes, unpub. data) cocirculate. In Peru, only genotype II has been identified. Genotype III has been reported only in Panama, whereas in Trinidad, only genotype I has been isolated
Genomics : 3 partite, single-stranded, negative-sense RNAs, named large (L), medium (M), and small (S) RNA. These RNAs are predicted to encode a large protein (L: polymerase activity), viral surface glycoproteins (Gc and Gn), and nonstructural NSM protein, as well as both nucleocapsid (N) and NSS proteins (Büchen-Osmond C, editor. ICTVdB management. New York: Columbia University; 2003). Complete nucleotide sequences have been determined for all 3 RNA segments^{ref1, ref2, ref3}, and previous studies of the molecular biology of the N gene (SRNA) of 28 different OROV strains indicated the existence of 3 genotypes, designated I, II, and III^ref.
Transmission : a zooanthroponosis ; vector : isolated from mosquitoes (Coquillettidia venezuelensis, Ochlerotatus serratus and Culex quinquefasciatus in Brazil) and frequently from the midge Culicoides paraensis
=> Oropouche fever : exanthema, fever, chills, malaise, headache, myalgia, and arthralgia, sometimes with nausea and nausea and vomiting, and occasionally with aseptical meningitis
• Facey's Paddock virus
• Iquitos virus : phylogenetic analyses of ORO-like strains isolated from febrile patients in Iquitos, Peru, identified a novel ORO reassortant virus, which the authors have named Iquitos (IQT) virus based on the location of the isolation of the virus. Iquitos is a city of about 380 000 inhabitants located 120 meters (394 feet) above sea level in the Amazon Basin in northeastern Peru. Genetic analyses of ORO-like strains from Iquitos, Peru, identified a novel reassortant containing the S and L genome segments of ORO virus and the M segment of a novel Simbu serogroup virus. This new pathogen, which is named Iquitos (IQT) virus, was 1st isolated during 1999 from a febrile patient in Iquitos, an Amazonian city in Peru. Subsequently, the virus was identified as the cause of outbreaks of "Oropouche fever" during 2005 and 2006 in Iquitos. In addition to the identification of 17 isolates of IQT virus between 1999 and 2006, surveys for neutralizing antibody among Iquitos residents revealed prevalence rates of 14.9 percent for ORO virus and 15.4 percent for IQT virus. Limited studies indicate that prior infection with ORO virus does not seem to protect against disease caused with the IQT virus infection. It is likely that IQT virus is transmitted by the same vectors as ORO^ref.
• Simbu virus
Epidemiology : isolated from Aedes circumluteolus and Eretmapoditeschrysogaster in Africa; serologically related species infect humans and other animals
• Tinaroo virus
=> acute encephalitis
• Phlebovirus / pappataci fever viruses are classified in 2 antigenic groups, the sandfly fever group and the Uukuniemi group. The sandfly fever group includes at least 39 species in nine serogroups and ungrouped species; the Uukuniemi group (the uukuviruses), which was previously recognized as a separate genus, contains 12 species in a single serogroup. The sandfly fever group includes the pathogens sandfly fever–Naples, sandfly fever–Sicilian, Toscana, and RVFV; most sandfly fever viruses are transmitted by sandflies of the genus Phlebotomus, but some are mosquito-borne. Uukuviruses are tick-borne and include no known human pathogens.
• Chagres virus : an arbovirus causing fever associated with malaise, headache, and pains of localized and generalized distribution, in Panama.
• Punta Toro virus
• Rift Valley fever virus (RVFV)
Epidemiology : RVF was first described in sheep in the early 20th century, and the virus was first isolated in humans in the Rift Valley of Kenya in 1930 (Daubney R, Hudson JR, Garnham PC. Enzootic hepatitis or Rift Valley fever: an undescribed virus disease of sheep cattle and man from East Africa. J Pathol Bacteriol 1931;34:545--79; Meegan JM, Bailey CL. Rift Valley fever. In: Monath TP, ed. The arboviruses: epidemiology and ecology. Boca Raton, Florida: CRC Press, Inc; 1989;IV:51--76). It is now seen throughout southern and eastern Africa to Egypt in epizootics occurring once in 10 - 15 years, mainly following periods of excessive rains. South Africa had a painful lesson in 1951, when RVF, previously unknown there, had its 6-month-long unhindered course throughout vast areas, infecting numerous animals and humans before being identified. RVF was initially recorded in southwest Mauritania and bordering north Senegal in 1987, following the opening of Diama Dam at the mouth of the Senegal River. The dam project created additional breeding grounds for mosquitoes carrying the disease, and initially resulted in > 200 human deaths from RVF. The last major outbreak of RVF in East Africa (Kenya and Somalia) occurred during 1997/98, also following heavy rains. During that time in Garissa District, around 27 500 were infected and 170 died. According to OIE's Handistatus data, Kenya reported 14 RVF outbreaks in cattle in 1999 but no outbreaks during 2000 or 2001. Egypt was the first country to be affected by RVF outside sub-Saharan Africa, namely in 1977, suffering one of the most devastating outbreaks in the history of the disease. During September 2000/first quarter of 2001, the disease spread outside the African continent, most probably from the Horn of Africa (into the Arabian peninsula in 1997/1998 during the RVF epidemic in East Africa via introduction of infected imported livestock or via windborne infected mosquitoes, and that climatic conditions have promoted sufficient vector populations to support transmission in Saudi Arabia and Yemen), into Yemen and southern Saudi Arabia (Jizan : > 125 deaths), affecting humans and animals (mainly small ruminants) : it might have become endemic in certain regions such as Jizan, with a risk of spreading to other generally less receptive regions, during certain seasons or under particular climatic conditions. The annual influx of over 2 million pilgrims for the Hajj (annual pilgrimage for Muslims) in Saudi Arabia, as well as the large migrant population in this region, generates high human and animal traffic that presents a challenging agenda for public health. As of Tue 30 Jan 2007, 411 suspected cases, including 121 deaths (case-fatality rate, 29 percent) have been reported in North Eastern Province, Coast Province, Eastern Province and Central Province. The North Eastern Province has been the most affected, with Garissa district (175 suspected cases, 58 confirmed cases, including 57 deaths) and Ijara district (125 suspected cases and 22 confirmed cases, including 23 deaths) reporting the most cases and deaths. Sporadic cases have also been reported from districts in Eastern Province (Isiolo - 8 suspected cases, 3 confirmed cases) and from districts in Central Province (Kirinyanga - 4 suspected cases, 4 confirmed cases, including one death; Kajiado - 3 suspected cases, one confirmed case, including 3 deaths; Maragua - one suspected case, one confirmed case); Thika - 2 suspected cases, one confirmed case). Some of the cases from Central Province were diagnosed in Nairobi^ref.  Eastern Kenya experienced unusually heavy rainfall during the period October to December 2006, three times the average for that period during the preceding 8 years and 13 times the rainfall in 2005 (Kenya Meteorological Department, unpublished data, 2007). Patients with RVF usually have initial signs and symptoms of influenza-like illness; < 8% of patients subsequently have severe disease, including generalized hemorrhagic syndrome, encephalitis, or retinitis (Meegan JM, Bailey CL. Rift Valley fever. In: Monath TP, ed. The arboviruses: epidemiology and ecology. Boca Raton, Florida: CRC Press, Inc; 1989;IV:51--76). The overall human mortality rate from RVF has been estimated at 0.5% to 1.0% of those infected, but the rate is much higher among those with severe disease. The largest reported human outbreak occurred in Kenya during the period 1997 to 1998, in which an estimated 89,000 persons (based on a systematic serosurvey) were infected and 478 died; this outbreak also was centered in NEP^{ref1, ref2, ref3}. Previous RVF outbreaks among humans were not reported outside sub-Saharan Africa until 1977 to 1978, when approximately 18,000 persons became ill with 1000 in Yemen had severe illness^{ref1, ref2} (El-Akkad AM. Rift Valley fever outbreak in Egypt, October--December 1977. J Egypt Public Health Assoc 1978;53:137-46). Like the 1997-1998 outbreak, the current outbreak was associated with heavy rainfall, which produced massive flooding in much of Kenya, and particularly in NEP. Climatic forecasting in conjunction with satellite imaging of flooded areas has been suggested as a method for predicting where and when RVF outbreaks might occur, potentially enabling earlier interventions^ref.
Transmission : a peracute or acute zooanthroponosis; reservoir : Ovis aries, Capra hircus, buffalo, camels and Bos taurus, transovarial transmission in Aedes mcintoshi, rodents. RVF may affect many animal species;  its primary amplifying hosts are sheep and cattle. The clinical signs vary with the age. In endemic regions, it can be recognized by the high mortality in newborn animals and abortions in adults; its mortality rate may reach 90 to 100% in neonates of sheep, and 10 to 70% in young calves. The symptoms in adult sheep may include fever, a mucopurulent nasal discharge (sometimes bloodstained), hemorrhagic or foul-smelling diarrhea, vomiting, jaundice, abortion and an unsteady gait. In adult cattle, fever, anorexia, weakness, excessive salivation, fetid diarrhea, abortion and decreased milk production may be seen. Similar but milder infections occur in goats. Infection from animal to man may be
• direct, by exposure of humans to aerosol spread of either the blood or other body fluids of infected animals. This exposure can result from the slaughtering or handling of infected animals or aborted foeti or by touching contaminated meat during the preparation of food
• vectors : Aedes albopictus, Aedes caballus, Aedes circumluteolus, Aedes vexans arabiensis, Culex theilesi, Culex pipiens, Culex fatigans, Culex tritaeniorhyncus, Mansonia spp., Eretmapoditeschrysogaster. In massive numbers, Phlebotomus spp., Simulium spp., Glossina morsitans, and Culicoides spp. may mechanically spread RVFV. Rift Valley fever virus  can be spread by at least  31 mosquito species, and moreover has been isolated from 2 tick species, including Rhipicephalus appendiculatus in Kenya, but mosquitoes remain the most important arthropod vectors. In Kenya isolations of the virus have been made from Aedes dalzieli, Ae. durbanensis, Ae. mcintoshi (formerly called Ae. lineatopennis), Culex antennatus, Culex theilesi, Cx. zombaensis, Cx. rubinotus, Anopheles christyi and An. pharoensis. At a guess  the most important vectors in Kenya  could Ae. mcintoshi and Cx. antennatus, both being common mosquitoes that bite humans and  which breed in pools and marshy areas especially those having grassy vegetation. Adults of Ae. mcintoshi bite mainly during the daytime, while those of Cx. antennatus bite mainly in the evenings and at night and therefore insecticide treated bednets could offer considerable protection, although if biting was experienced early in the evenings before people had gone to bed they would be exposed to transmission. But what is needed is the identification of the species transmitting RVF so that most appropriate actions can be taken to reduce transmission. Also Aedes circumluteolus, a common mosquito in Kenya, is a known vector of RVFV in both Uganda and South Africa, but I am unsure whether it is a proven vector in Kenya.
• exposure to body fluids (particularly freshly shed blood or amniotic fluid from aborting animals) or freshly dead meat of infected animals. It is generally believed that meat from carcasses inactivates RVFV through post-mortem acidification. This route is common in farmers, farm laborers, and abattoir personnel. Exposure of humans to infected animal tissues may specifically occur when exposed to blood aerosols during the slaughter of viraemic animals, e.g. in the massive slaughtering of ruminants during :
• the Moslem holiday
• Eid al-Fitr holiday, also called Eid al Zeghir (minor festival). Eid al-Fitr marks the end of Ramadan, the Muslim holy month of fasting, and is celebrated during the first 3 days of Shawwal, the 10th month of the Islamic calendar. During these days, house slaughtering of ruminants, mainly sheep and goats, is widely practiced, especially in rural areas. Eid al-Fitr is due in 2004 on 14-15 November -- a season characterised by intense vector activity in the Near East. Vector control activities might help, but timely mass vaccination of susceptible ruminants is essential in order to prevent the establishment of RVF in animals and the subsequent public health hazard.
In April 2004, the Saudi authorities lifted a 3 year old ban on the movement of livestock between regions hit by RVF. The ban was imposed on animals in Jizan, the Tihama areas of Asir, Makkah [Mecca], as well as Baha regions Qunfudha, Najran, and Tihama Qahtan. The Agriculture Ministry set up an early-warning unit "to monitor and contain infectious diseases that affect agricultural and animal resources in certain regions, before those diseases spread to other parts of the Kingdom" and established a laboratory in Jizan to carry out medical tests and check the effectiveness of insecticides. Although it is stated that Aedes species are the main vectors, considerable transmission can be due to Culex and Mansonia species. In Kenya, species found naturally infected include Aedes dalzei, Ae. durbanensis, Ae. lineatopennis, Culex antennatus, Cx. simpsoni, Cx. vansomereni, Cx. zombaensis, Cx rubinotus and Anopheles christyi and An. pharoensis. Note the large numbers of Culex species. In addition, the tick Rhipicephalus appendiculatus was reported as a vector in Kenya in 1933. In Nigeria (1967) Culicoides species were reported positive for the virus as were Simulium species in South Africa in 1953. However, whether these non-mosquito vectors are important epidemiologically is questionable. I would guess not. Whereas the eggs of Aedes mosquitoes can tolerate desiccation for months and even years, species of Culex and other genera cannot. Transovarial transmission was shown in Ae. lineatopennis in Kenya and in Ae. vexans in Senegal, but most likely occurs in other aedine species. It has been suggested that such transmission maintains the virus in nature during inter-epidemic periods. Recent epidemics in Kenya have shown the importance not only of rainfall but also of crop irrigation practices. If logistics and finances allow, then ultra-low-volume (ULV) aerial applications of insecticides are the most appropriate method for curtailing epidemics; or on a smaller scale, ground-based spraying can be used. Commonly used insecticides include organophosphates, such as malathion and pirimiphos-methyl, or pyrethroids, like permethrin and deltamethrin, to kill the adults. Insecticide-impregnated nets, which can remain effective for many months or even years depending on the method of treating the nets with pyrethroid insecticides, will only be effective at night, when people are sleeping under them. Many of the potential RVF vectors (e.g. most Aedes species) bite during the daytime, not at night, although in general, Culex, Mansoniaand Anopheles species bite at night. Indoor residual spraying, whether in human or animal quarters, will only be effective if the vectors enter such quarters to feed and or rest, and most potential vectors do not. By the way, one hopes that Kenya will soon reintroduce DDT spraying of houses for malaria control, as have at least 8 other African countries. What is meant by larviciding stagnant pools? Many, if not most, RVF vectors will not breed in stagnant waters but in relatively clean aquatic habitats. Moreover, larviciding needs precise identification of the aquatic habitats colonized by vector mosquitoes, which, combined with the often extensive nature of such habitats, means that larviciding is not likely to be very effective. Moreover, when desiccated eggs are flooded, not all will hatch; it may take several repeated flooding and drying periods to stimulate hatching. Larviciding will kill only the larvae, not any un-hatched eggs.
=> Rift Valley fever (RVF) : the incubation period is 2-6 days : human infections are quite frequent
• most people with RVF have no symptoms or influenzalike symptoms with liver abnormalities
• classic hemorrhagic fever with fever, chills, headache, myalgia, weakness, diarrhea, nausea and vomiting, and hemorrhages, back pain, dizziness, and rapid weight loss lasting 4 to 6 days with slow recovery within 2 days to one week The most common complication associated with RVF is retinal vasculitis. As a result, 1-10% of affected patients may have some permanent vision loss
• 1-2 % : severe disease with hepatitis and liver necrosis, hemorrhagic pneumonia, and acute meningoencephalitis (CFR = 10-36%)
In livestock, RVF causes abortion and death. Livestock epizootics can occur after heavy rainfall and flooding that result in hatching of Aedes mosquitoes (thought to be the initial vector and inter-epizootic reservoir of RVF) and other vectors that feed on nearby mammals^ref. Direct exposure to infected animals can occur during slaughter or through veterinary and obstetric procedures.
Laboratory examinations : serology
Prognosis : the overall mortality from RVF is not known with precision, but may be around 1%
Therapy : IV ribavirin
Prevention : killed vaccine.
• sandfly fever Naples virus (SFNV)
• Tehran virus
• Toscana virus (TOSV)
Epidemiology : 25% seroprevalence rate is similar in Mediterranean areas^{ref1, ref2, ref2} (cases of severe lymphocytic meningitis were been observed in adults in the South of France, especially in Marseille, during August 2005). Other seroprevalence studies carried out in northern Europe report lower rates^ref, which demonstrates that TOSV infection is endemic in residents and visitors from Mediterranean countries^{ref1, ref2, ref3, ref4, ref5, ref6, ref7}. In Spain, the first TOSV infections involving the central nervous system were reported in Granada in 1988^ref. Later, cases of TOSV infections were detected in other areas of Spain^ref. Phylogenetic analysis of short polymerase chain reaction (PCR) products from the L segment showed that nucleotide sequences of TOSV isolates from Granada differ significantly from the Italian strain ISS Phl.3^ref. In 2014 a novel variant of TOSV has been detected in Greece
Transmission : a zooanthroponosis ; vector Phlebotomus papatasi, TOSV was first isolated in Italy from the sandfly Phlebotomus perniciosus and later from Phlebotomus perfiliewi^ref (Verani P, Lopes MC, Nicoletti L, Balducci M. Studies on phlebotomus-transmitted viruses in Italy. Isolation and characterization of a sandfly fever Naples-like virus. In: Vesenjak-Hirjan J, Porterfield JS, Arslanagic E, editors. Arboviruses in the Mediterranean countries. Stuttgart: Gustav Fischer Verlag; 1980. p. 195–201). P. perniciosus is the most abundant anthropophilic species of Phlebotomus in Spain (Gil-Collado J, Morillas-Márquez F, Sanchis-Marín MC. Los flebotomos en España. Revista de Sanidad e Higiene Publica. 1989;63:15–34). The maximum activity of sandfly vectors for TOSV occurs during summer, along with most cases of TOSV infection^ref
=> sandfly fever (SF) : brief, self-limiting high fever, headache, myalgia; rarely acute aseptic meningitis and meningoencephalitis. Although TOSV is not normally associated with mild disease, serologic studies report high seroprevalence rates in areas of confirmed TOSV infections^{ref1, ref2, ref3}. Furthermore, a case of influenza-like illness caused by TOSV has recently been reported^ref. The high seroprevalence rates suggest that the diagnosis of TOSV infection is frequently missed since most cases are mild, as occurs with SFSV and SFNV infections^ref, a severe illness involving the central nervous system develops in only a few patients. Despite this, fewer cases of severe disease caused by TOSV occur in Granada area^ref than in other countries^ref. A possible explanation for this could be that Spanish TOSV are less neurovirulent than the Italian. Whether changes in other parts of the genome, such as the noncoding regions, affect the neurovirulence of this virus, as described for tickborne encephalitis virus^ref, needs to be investigated^ref
=> sandfly fever (SF)