HOMO SAPIENS DISEASES - SUBCELLULAR LIFE FORMS
(see also Physiology of subcellular life forms and Antimicrobials for viruses)

Table of contents :

  • Viruses => viroses
    		•  Generalities for viroses
    Web resources

    Our guts are teeming with 1,200 different viruses, > 50% of which are unknown to science : most are bacteriophagesref. Some 99% of the world's bugs cannot be grown, or therefore identified, in the laboratory

    Viruses

    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 :
    Epidemiology : identified in 2011 in a skin swab sample from a healthy donor, similar to the chicken anemia virus (CAV), the only previously known member of the Gyrovirus genus. In particular, this virus encodes an homolog of the CAV apoptin, a protein that selectively induces apoptosis in cancer cells. By PCR screening, HGyV was found in 5 of 115 other non-lesional skin specimens, but in none of 92 bronchoalveolar lavages or nasopharyngeal aspirates and in none of 92 fecal samplesref.
    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 Peruref
    Epidemiology : was first isolated in Nigeria in 1966 during surveys of livestock, Culicoides midges, and mosquitoes, SHUV also once was isolated from a febrile childref1, ref2. SHUV recently was identified as a previously undetected cause of neurologic disease in horses in southern Africaref and veterinarians in South Africaref and is thus of interest in comparison to WNV.
    Epidemiology : in 2009 >150 human infections in 16 Chinese provinces and to have an associated death rate of ≈12%ref1, ref2. Fatal SFTSV infections were reported in humans in Japan in 2012ref and South Korea in 2012ref.
    Transmission     : isolated from blood of 2 patients and from Haemaphysalis ticks (Anaplasma phagocytophilum) collected from dogs. Isolation of the virus from ticks does not prove their vector capacity, nor from dogs indicates that they are competent sources of infectious blood meals for arthropod vectors, but these findings do indicate that laboratory susceptibility and transmission experiments are worth doingref1, ref2

    Epidemiology : in June 2009, in northwestern Missouri, United States, 2 men from 2 geographically distant farms were hospitalized for fever, fatigue, diarrhea, thrombocytopenia, and leukopenia. Both men had been bitten by ticks 5–7 days before the onset of symptoms. A virus was isolated from the leukocytes of each patient and later identified as a novel phlebovirus by next-generation sequencing. The 2 viruses were highly related (98%, 95%, and 99% sequence identity for the small, medium, and large viral genome segments, respectively), indicating that the men were independently infected with the same virusref.
    • Hunter Island Group virus (HIGV)
    Epidemiology : isolated retrospectively in 2014 during the investigation of a disease outbreak among shy albatrosses in Tasmania in 2002ref
    Transmission : ticks (Ixodes eudyptidis)
     The name is derived from the patient's initials (G.B.).
    Epidemiology : first identified in 2012 as the causative agent of a lethal pneumonia in several patients in the Middle Eastref. As of July 10, 2013, a total of 80 cases have been identified in the Middle East (Saudi Arabia, Jordan, Qatar, and the United Arab Emirates), Europe (United Kingdom, France, Italy, and Germany), and North Africa (Tunisia), with a case fatality rate of 56%. Soon after the identification of MERS-CoV, information about its genomic sequence and organization, species tropism, and host-cell receptor (dipeptidyl peptidase 4) was publishedref1, ref2. These initial studies did not identify the source of this newly identified virus, nor did they reveal whether MERS-CoV could be transmitted from human to human, a requirement for designation as an epidemic disease. In this issue of the Journal, Assiri et alref. describe the largest outbreak of MERS-CoV infection thus far, showing that the virus is transmitted from human to human. This outbreak occurred in several hospitals in the governorate of Al-Hasa in eastern Saudi Arabia, with transmission probably occurring in dialysis units, intensive care units, and wards. Most patients had underlying diseases, with a remarkable number (17 of 23) having diabetes. In addition to showing that human-to-human transmission occurred frequently, the relatively large number of patients infected in this outbreak made it possible to define characteristics of the infection, such as the incubation time (5.2 days) and the serial interval (7.6 days). As seen in the SARS epidemic, there was variability in the numbers of patients infected by each index patient, with 1 patient transmitting virus to 7 contacts; superspreading events, in which a few patients infected large numbers of contacts, were critical factors in SARS reaching epidemic proportions. MERS-CoV has the potential to spread widely within health care settings, infecting primarily other patients but also health care workers and family contacts, although to a lesser extent. Patients with diabetes or chronic renal failure appear to be at especially high risk for severe MERS-CoV infection, but whether these coexisting conditions represent true risk factors or whether these patients happened to be preferentially exposed to index cases is not known, given the relatively small number of infected patients. Also unclear from this study is the extent to which MERS-CoV infection is a systemic disease. Acute renal failure developed in several patients with the infectionref1, ref2, ref3, ref4, possibly reflecting a high level of dipeptidyl peptidase 4–receptor expression in the kidney. However, in the absence of tissue samples obtained at surgery or autopsy, it has been difficult to determine the extent to which kidneys or other organs are infected. Although the report by Assiri et al., as well as others in the Journal and elsewhereref1, ref2 indicates that human-to-human transmission occurs, at least in the context of close contact, many additional questions related to the transmission of MERS-CoV and its ability to reach epidemic proportions are unanswered. On one hand, coronaviruses are notorious for rapid adaptation to new hostsref, a finding that is best illustrated by the ability of SARS-CoV to adapt to replication in the human lung. Adaptation involved changes in the surface glycoprotein, which is responsible for binding to the host-cell entry receptor, and in proteins involved in viral replicationref. Additional adaptation of MERS-CoV to human populations, although not observed thus far, is likely to occur and would augment the possibility of widespread infection. Furthermore, the community (probably zoonotic) source for MERS-CoV remains unknown, making it difficult to know whether periodic reintroduction into human populations will occur and contribute to the potential for human adaptation. Moreover, the relative importance of aerosol transmission versus spread by large droplets or contact is unknown, but the mode of transmission will affect the likelihood of large-scale human infection. On the other hand, an epidemic is not a certainty, since a first set of statistical analyses —performed with the use of all the available data on human-to-human transmission, including those in the study by Assiri et al. — suggests that MERS-CoV does not now have pandemic potentialref. Thus, in the absence of further adaptation or repeated introduction from community sources, widespread infection may not develop. The prevention of future spread of the epidemic will require careful surveillance and testing of patients with pneumonia living in the Middle East or with a history of recent travel to affected regions. Current virus detection is based on polymerase-chain-reaction testing, with sensitivity depending on the viral load at the time the specimen is obtained. Some studies show that the virus is most readily isolated from specimens obtained from the lower respiratory tractref1, ref2 and since the course of clinical disease is not yet well defined, diagnosis may require repeated testing. It is also essential to determine the prevalence of MERS-CoV seropositivity in human and animal populations in Saudi Arabia and elsewhere in the Middle East to establish the likelihood of an epidemic and also to prevent one from occurring. This information is critical for an effective public health response. In addition to requiring vigilance by health care workers and public health authorities, obtaining these data is dependent on the generation of a validated serologic assay, which is not currently available. An immediate concern is that the MERS-CoV will infect pilgrims traveling to Saudi Arabia this October for the Hajj pilgrimage. Fortunately, last year's Hajj did not result in an increase of patients with MERS-CoV infection. Obtaining a favorable outcome this year will require the same good fortune and will be facilitated by careful vigilance and management of cases and contacts.
    Receptor : DPP-IV
    Therapy : RBD-specific neutralizing monoclonal antibodies (MERS-4 and MERS-27) derived from single-chain variable region fragments of a nonimmune human antibody libraryref.

    => 5-17% of all acute rhinitis
    => pharyngotonsillitis
    => acute laryngitis and epiglottitis
    => acute bronchitis
    Epidemiology : 1st isolated in California in 1962 from 4 children with bronchiolitis and pneumonia, HEV68 has been reported rarely since that time and the full spectrum of illness that it can cause is unknown. The 6 clusters of acute respiratory distress associated with HEV68 described in this report occurred in Asia, Europe, and the United States during 2008-2010. HEV68 infection was associated with respiratory illness ranging from relatively mild illness that did not require hospitalization to severe illness requiring intensive care and mechanical ventilation. 3 cases, 2 in the Philippines and one in Japan, were fatal. In these 6 clusters, HEV68 disproportionately occurred among children. The CDC learned of clusters of HEV68 from public health agencies requesting consultation or diagnostic assistance and from reports presented at scientific conferences. In each cluster, HEV68 was diagnosed by reverse transcription-polymerase chain reaction (RT-PCR) testing targeting the 5'-nontranslated region, followed by partial sequencing of the structural protein genes, VP4-VP2, VP1, or both, to give definitive, enterovirus type-specific information. This report highlights HEV68 as an increasingly recognized cause of respiratory illness. Clinicians should be aware of HEV68 as one of many causes of viral respiratory disease and should report clusters of unexplained respiratory illness to the appropriate public health agency.
    => diarrhea in Japanref, Indiaref and Thailandref
  • Betaretrovirus / mammalian type B retroviruses : a genus having a characteristic dense core 40–60 nm in diameter enclosed by a membranous envelope 90–120 nm in diameter with prominent surface spikes; capsid assembly occurs in the cytoplasm prior to budding from the plasma membrane
    • mouse mammary tumor virus (MMTV) / Bittner virus
      Transmission : from mother to offspring through the infected milk before the stomach is acidified => invasion of Peyer's patches => MMTV SAg induces a proliferative B cell response, amplifying the pool of infectious and susceptible B cells, which transmit the virus to the mammary gland just before infecting the mammary epithelium
      endogenous noninfectious MMTV particles are transmitted as part of the germline DNA
      not infectious for other mice
      => 95% of mammary adenocarcinomaref and lymphomas in certain strains of mice. Although both exogenous and endogenous forms of the virus appear able to induce mammary carcinogenesis independently in some mouse strains, they may also combine and be carcinogenic in the breastref. This phenomenon of recombination of exogenous and endogenous retroviruses, which then induce cell proliferation, is known in other virusesref ; glucocorticoids, insulin, EGFs, oestrogens and progestins synergize with MMTV in genetically susceptible female mice to cause mammary cancers
    • unclassified Betaretrovirus
      • Human mammary tumor virus ( HMTV) / human homologue of the mouse mammary tumour virus (HHMMTV) in humans is 90% similar to the mouse virus
        • => fragments of MMTV-like DNA are found in up to 75% of biopsy samples taken from women with breast cancer : > 70% of 38 Tunisian samplesref , 42.2% of Caucasian-Australian women who have breast carcinoma, 38% from USA and Italian women, 31% from Argentinian women, 0.8% from Vietnamese and Vietnamese-Australian women (this roughly corresponds to the distribution of the virus-carrying house mouse, Mus domesticus, which is extremely common in North Africa but less so in the United States and elsewhere). It is important to spot whole virus particles, rather than fragments, inside the breast cancer samples. Then the virus needs to be isolated and proven to infect animals and cultured human breast cells. 3 distinct Xac strains are known, based on serology and DNA analysis. The virus is only found in the cancerous tissue in the breast, but not in the non-cancerous tissue of the same breast. In non-cancerous cases, the virus appeared in < 4% of the samples (2 out of 111 patients), but at a follow up 8 years later, both had had breast cancer. Over 50% of male breast carcinoma samples test positive for HHMMTV and an antigen that is related to MMTV has been identified in approximately 90% of human male mammary carcinomasref. A high number of non-cancerous diseases of the breast that are thought to increase the risk for subsequent breast cancer have also been shown to be positive for the virus. The next step is to establish whether the virus is causing the cancer, or if the cancers provide a good place for the virus to live and multiply. Serum of humans with breast cancer decreased the virility of MMTV, which suggested that antibodies to proteins of the virus may be present in humansref.Antibodies that are reactive with MMTV are present at much higher levels in serum of humans with breast cancer than in serum of healthy women. Such antibody levels in women with breast cancer vary from below 5% (in Chinese) to over 60% (in East Africans) among different populationsref. In addition, the geographic variation in human breast cancer parallels the presence of the wild, but common Mus musculus, which may have acted as an animal host of the MMTVref. MMTV env gene sequences were found in 30-40% of breast cancer tissues in women from various populations. The INT6 gene is a common integration site for MMTV in mouse mammary tumours, and a human homologue (eIF3 subunit 6) is expressed human breast cancer tissues. Administration of oestrogen followed by progesterone stimulates the expression of human endogenous retroviruses in the genome. There is seemingly strong evidence against a infectious cause of some types of breast cancer that is transmitted by mothers milk. Breast cancer rates are low in countries where breast-feeding is prolonged, and rates are increasing in countries where breast-feeding is declining; breast cancer occurs equally in maternal and paternal lines; and mother and daughter occurrences of breast cancer are not associated with breast-feeding. In addition, in a recent, large, case-control study of over 5685 US women with breast cancerref, no evidence was found that having been breast-fed increased breast cancer risk in either premenopausal or postmenopausal women. An implication of this study is that human mothers' milk does not transmit an infectious agent. However, it was also observed in that study that women with breast cancer had a strong familial history of breast cancer, an observation that is compatible with an endogenous virus transmitted with germline cells, which may influence carcinogenesis in genetically susceptible individuals.
        => non-Hodgkin's lymphoma (NHL)ref (which occurs more frequently in women with breast cancer than in the general populationref)
  • Deltaretrovirus [BLV-HTLV retroviruses : a genus similar in morphology and replication to the type C retroviruses; organisms have a long latency and cause B and T cell leukemia and lymphoma and neurological disease] : they are transmitted horizontally, and no endogenous counterparts are known. So far, they have been found only in bovines and primates. They are associated with B- or T-cell leukemias or lymphomas, and neurological disease (tropical spastic paraparesis or HTLV-associated myopathy). Unlike other oncogenic retroviruses, deltaretroviruses have an additional region, tax (trans-activating region of the X gene), which has regulatory functions and is oncogenic to host cells. tax causes malignant transformation not through integration and insertional mutagenesis, as many retroviruses do, but by inhibition of DNA repair (base excision pathway) and trans-activating disruption of cellular growth control mechanismsref. Previously, it was thought that the present distribution of HTLV 2 in the world reflected its possible introduction into the New world at the time of the initial settlement of the American continent by the ancestors of the present day native Americans some 20 000 to 40 000 years ago, followed by more recent dissemination from one or a few centers. It seems more likely now, in the light of the above evidence, that all 4 primate T-lymphotropic viruses were transmitted to humans from African primates
    • Epidemiology : bovine leukosis (B-cell leukemia/lymphoma), first described in 1871 in Lithuania, was believed to be an infectious disease because it spread through herds of cattle. In 1969, a virus isolated from cultured lymphocytes of cattle in an afflicted herd was identified as the agent of bovine leukosisref.
    Pathogenesis : an oncogenic retrovirus that commonly infects cattle and causes a significant polyclonal expansion of CD5+, IgM+ B lymphocytes known as persistent lymphocytosis (PL) in approximately 30% of infected cattle. There is evidence that this expanded B cell population has altered signaling, and resistance to apoptosis has been proposed as one mechanism of B cell expansionref, eventually leading to B cell leukosis in 1-5% of infected cattle. BLV-infected cattle herds are found worldwide. In the United States, ≈38% of beef herds, 84% of all dairy herds, and 100% of large-scale dairy operation herds are infectedref1, ref2. Cattle with leukosis are excluded from the market as a resultref, but BLV-infected lymphocytes are also found in the blood and milk of subclinically infected cowsref.
    Transmission : BLV-infected cells are present in marketed beef and dairy products. In the decade after the discovery of BLV in 1969, studies using agar gel immunodiffusion and complement fixation assays failed to find antibodies to BLV in human sera. This led to the prevailing opinion that exposure of humans to BLV and/or the potential for infection are not significant and therefore the virus is not a public health hazard. A group reexamined this issue using more sensitive immunological techniques available today. Concerns that this virus might infect humans through exposure to food products from subclinically infected animals prompted 10 studies that used what were then (1975–1979) state-of-the-art immunologic methods to test serum samples from a collective total of 1,761 humans, including cancer patients, farm workers, and veterinariansref. In these studies no antibodies against BLV were detected, prompting Burridge to conclude in his review article, “There is no epidemiological or serological evidence from human studies to indicate that BLV can infect man”ref. The advent of immunoblotting, ≈100 times more sensitive than techniques of the 1970sref, enabled the detection of antibodies reactive with recombinant purified BLV p24 capsid protein in serum samples from 39% of 257 self-selected human volunteersref. This study could not determine whether the antibodies were a response to infection or merely to heat-inactivated BLV consumed in food products. However, injection of sheep with raw milk from BLV-positive cows stimulated antibody production, whereas injection with pasteurized control milk did notref1, ref2. The finding of antibodies to BLV in humans prompted us to investigate human tissues for evidence of infection with BLV by using liquid-phase PCR (L-PCR), sequencing, in situ PCR, and immunohistochemical (IHC) testing. Buehring et al focused on breast tissue because, in cattle, BLV DNA and p24 were detected in mammary tissue, whereas only BLV DNA was detected in lymphocytesref. In situ PCR and immunohistochemical testing localized BLV to the secretory epithelium of the breast. Our finding of BLV in human tissues indicates a risk for the acquisition and proliferation of this virus in humans. Further research is needed to determine whether BLV may play a direct role in human diseaseref.
    • primate T-lymphotropic virus 1
        • Epidemiology : isolated 1st from a cell line derived from splenic cells taken from a patient suffering from a hairy cell leukemia, now considered to be a fortuitous association. HTLV-1 was first isolated and identifiedref from a patient with a cutaneous T cell malignancy. Similarities in the clinical picture and the abnormal T cell morphology led to the suggestion that HTLV-1 was also involved in ATL, which had been described in Japan a few years earlierref. Subsequent seroepidemiological and molecular work confirmed this connectionref1,ref2, ref3, ref4, ref5, ref6. Prevalence : 10-20 million people worldwideref. HTLV-1 is widespread in the tropics and subtropics. There are large endemic foci in the Caribbean, southern Japan, central and South Africa, and South America, particularly Brazil. HTLV-1 is also present in southern Africa, southern India, northern Iran, the aboriginal populations of northern Australia, and many islands in the tropics. In Europe and North America, the virus is found chiefly in certain immigrant groups and in intravenous drug users. Within the endemic areas, the distribution of HTLV-1 is typically uneven: the seroprevalence varies widely, between 0.1% and 30% of adults, often with great differences between neighbouring towns. There is an unexplained predilection for coastal areas.
        • Canada : 20 cases discovered since June 2005 in a person with leukemia, publicly announced on Fri 30 Sep 2005. HTLV-1 is so rare in Canada that it's not a reportable disease in many jurisdictions. The last outbreak in memory was in 1993, when 3 people were found with HTLV-1 in British Columbia. The Canadian Blood Service, which has screened for HLTV-1 since 1990, reports that, out of roughly 900 000 blood donations received every year, only 10 or 12 are found contaminated with HLTV-1. HTLV-1 testing will also be added to prenatal screening tests. Previously, it was thought that the present distribution of HTLV-2 in the world reflected its possible introduction into the New world at the time of the initial settlement of the American continent by the ancestors of the present day native Americans some 20,000 to 40,000 years ago, followed by more recent dissemination from one or a few centers. It seems more likely now that all 4 primate T-lymphotropic viruses were transmitted to humans from African primates. It is likely that HTLV-1 was introduced into Nunavut Territory by a blood-borne or sexual route.
        • UK : between 2002 and 2004, 251  individuals were diagnosed with HTLV-1 and 1 with an HTLV-1&2 co-infection, the majority among those of black Caribbean ethnicityref1, ref2, ref3, ref4, ref5
        Genomics : antisense viral gene product HTLV-1 b-ZIP protein (HBZ)ref counteracts the transcriptional transactivation mediated by the HTLV-1 Tax oncoprotein by interfering with the DNA binding activity of JunB and c-Junref. Although adult T-cell leukemia (ATL) cells often contain deletions of the HTLV-1 proviral sequences, the 3' end of the provirus encompassing the Tax gene is invariably maintained in leukemic cells from patients. HBZ protein function is distinct and separate from any potential siRNA effects, as was recently described for the antisense transcript encoded in the 3' end of the HIV-1 provirusref. HBZ may function synergistically with the HTLV-1 accessory protein p30II to govern and throttle the transcriptional transactivation mediated by the Tax oncoprotein and that these activities provide a selective advantage in the maintenance of infection in vivoref.
        U5 repressive element is bound by zinc finger protein 282. HTLV-1 related endogenous sequence (HRES1) and HRES2 in human genome. In vivo HTLV-1 appears to integrate preferentially into chromosomes 7 and 17ref and rearrangements involving these chromosomes have been noted in adult T-cell leukemia cells. H1 strain was acquired from Papio, H2 from chimpanzee, and H3 from macaque. The genome of 9032 nucleotides contains the gag, pol, and env genes found in replication competent exogenous retroviruses.
        Proteomics : like other retroviruses, it has an envelope derived from the host cell membrane, and 2 copies of the positive sense RNA genome.The host cell infected by HTLV-1 is the CD4+T cell (Th cell). Many other human cell types can be infected in vitro, but appreciable productive replication occurs only in the CD4+ T cell.
        • receptor : HTLVRref, GLUT-1ref. The cellular receptor for the virus has been mapped to chromosomeref but has not yet been identified. ICAM-1, ICAM-3, and VCAM also facilitate entry of HTLV-1 into the cell, but are not the main receptors for the virusref1,ref2. Up-regulation of the HTLV receptor, via signals transmitted through the IL-7R as well as the TcR, is likely to contribute to the mother-to-infant transmission and spreading of HTLV-1ref
        • p19MA
        • p24CA
        • p15NC
        • RT
        • IN
        • env : gp46 + gp21
        • p12' binds b and g chains of IL-2R in cytoplasmic vesicles inducing STP to the nucleus via STAT5. It also binds calreticulin and calnexin, indirectly activating NF-AT
        • p13
        • p21
        • p30" is a post-transcriptional negative regulator of viral replication : by blocking expression of Tax and Rex it allows latency, indirectly favoring tranformation
        • non-structural, regulatory proteins :
          • p27Rex (homolog to HIV-1 Rex), the regulator of viral mRNA splicing
          • p40Tax (homolog to HIV-1 Tat, which binds to RNA) binds 3 CRE-like Tax-responsive elements (TRE) on vDNA LTR, facilitating dimerization of CREB, p300/CBP, activating transcription factor 4 (ATF4) / tax-responsive enhancer element B67, and pCAF to allow viral genome transcription. Further it transactivates cellular genes (e.g. IL-2, fucosyltransferase 7 IL-2Ra, vimentin, protoncogenes and transcription factors), while down-regulating expression of DNA polymerase II and p53. It inhibits p16INK4A and allow CDK4 to bind cyclin D. Tax interacts with MEKK and IKKg (indirectly activating NFkB and SRF), IL-16 and N3 and C9 subunits of 26S proteasome, and represses Smad-mediated TGF-b signaling. The Tax protein is required for replication of the virus. It is also strongly implicated in the leukaemogenesis that leads to ATLref1, ref2, and it is the chief target antigen recognised by the strong cytotoxic T lymphocyte response to the virus. As well as activating the transcription of HTLV-1 genes, Tax also induces expression of many cellular genes, including those encoding IL-2, the IL-2R, GM-CSF, TNF-a, and othersref. An understanding of the Tax protein is therefore essential for an understanding of the biology of the virus and its associated diseases. It immortalizes T lymphocytes in vitro into an IL-2-dependent state but can't transformate them into an IL-2-independent state (at the bet it synergize with actual v-onc) : transformation relies on ...
        Pathogenesis : chronic infection; infected cells secrete biologically active forms of MMP-9, VEGF and bFGF and induce angiogenesis in vitro. Perturbations in glucose metabolism resulting from interactions of HTLV envelope glycoproteins with GLUT-1 are likely to contribute to HTLV-associated disorders. On the contrary of HIV-1, HTLV viremia is never extracellular, there are low viral loads, and triggering of CD3/TcR leads to down-regulation of viral gene expression. The proviral load of HTLV-1 is unusually high compared with other retrovirus infections: a typical healthy carrier of HTLV-1 carries the provirus in about 0.1–1% of peripheral blood mononuclear cells (PBMCs). However, the provirus load is, on average, even higher in the chronic inflammatory diseases such as HAM/TSP, ranging up to 30% of PBMCsref1, ref2, ref3, ref4. The proviral load appears to be stable over many years in most individuals. In a recent case control study in Japan, the prevalence of HAM/TSP rises very sharply once the proviral load exceeds 1% of PBMCsref. This association between HAM/TSP and a high proviral load of HTLV-1 has been recognised for several years, and it is widely believed that healthy carriers of HTLV-1 with a high proviral load carry a high risk of progression to disease. Preliminary data from an 8 year prospective cohort follow up study of healthy HTLV-1 carriers are consistent with this viewTaylor GP, 92-100 but large scale, long term studies are needed to reach a definitive conclusion. These observations suggest that a high proviral load plays an important part in the aetiology of the inflammatory diseases. The 2 main questions that arise are: (1) What determines the proviral load "set point" in each individual? In particular, does the immune response play an important role? (2) How does a high proviral load cause HAM/TSP and the related conditions? Because there appears to be no neuropathic strain of HTLV-1ref, (Bangham CRM, 41-8) the different disease manifestations of HTLV-1 infection must be attributable to differences in host susceptibility or resistance to the virus. Therefore, to answer these questions we must first understand something of the immune response to HTLV-1. HAM is associated with a lower expression (compared with that in asymptomatic HTLV-1 carriers and healthy donors) of Foxp3 in peripheral-blood leukocytes : in individuals infected with HTLV-1, Foxp3 expression was inversely correlated with HTLV-1 tax proviral DNA loadref.
        Immune response : antibodies against the Gag protein of HTLV-1 (mainly p24) are the first to appear after infection, and predominate in the first 2 months, followed by anti-Env antibodiesref. About 50% of individuals subsequently produce antibodies to the Tax protein. The cellular immune response has not been studied systematically in the early stages of infection with HTLV-1. However, in the chronic phase, most infected individuals make a very strong cell mediated immune response to the virusref. The cytotoxic T lymphocyte (CTL) response to HTLV-1 has been studied in particular detail, because animal experiments in many virus infections indicate the special importance of these cells in limiting viral replication. In addition, the mononuclear cell infiltrate found in the spinal cord in the areas of demyelination consists predominantly of T cells, which are mainly CD8+ (the usual phenotype of antiviral CTLs), at least in the chronic phaseref1, ref2, ref3. Anti-HTLV-1 CTLs are unusual in their extreme abundance: up to 10% of circulating CD8+ T cells can recognise just one epitope of the virusref1, Daenke S, 139-46, ref3. The anti-HTLV-1 CTLs are unusual in 2 further respects: they are chronically activated, and most recognise a single viral protein, the Tax proteinref. How does the virus persist in the face of such a strong immune response? Specifically, do mutations in the Tax protein lead to escape from recognition by CTLs? Putative CTL escape mutations in Tax were indeed identified by Niewiesk et al.ref However, the selection pressure on the tax gene, presumably exerted by the Tax specific CTLs, was only evident in the healthy carriers of the virus, not in the patients with HAM/TSPref1, ref2. The HTLV-1 specific CTLs might play an important part in limiting the replication of the virus, so determining the individual's proviral load of HTLV-1 and their risk of inflammatory diseases such as HAM/TSPBangham CRM, 41-8, ref2. This conclusion suggested in turnBangham CRM, 41-8 that individual variation in the "efficiency" or "strength" of the anti-HTLV-1 CTL response might explain why some HTLV-1 infected people develop a high proviral load and diseases such as HAM/TSP, whereas others effectively suppress the replication of HTLV-1 and remain healthy. Patients with HAM/TSP in Kagoshima (in southern Japan) who carry HLA-A*02 (HLA-A2) allele have only half the risk of developing HAM/TSP as those who lack this alleleref. Because HLA class I genes are known to determine the specificity of CTLs, this observation suggests that HLA-A*02 restricted CTLs are particularly efficient at controlling HTLV-1 replication, and strongly supports the hypothesisBangham CRM, 41-8 that the CTL response to the virus is an important determinant of the risk of disease. In further support of this conclusion, healthy carriers of HTLV-1 who possessed the HLA-A*02 allele had a significantly lower proviral load of HTLV-1 than those who lacked this allele.66 Because HLA-A*02 is common in Kagoshima, as in all major human populations, its protective effect is very important at the population level: the presence of HLA-A*02 at its observed frequency prevents approximately 28% of potential cases of HAM/TSP in Kagoshimaref. The results of this study also confirmed previous indicationsref1, ref2 that the class II HLA gene, HLA-DRB1*0101 (HLA-DR1) appears to increase the risk of HAM/TSP; the reason for this association is not yet explained. However, the predisposing effect of HLA-DRB1*0101 is seen only in people who lack HLA-A*02. That is, the HLA-A*02 associated protection appears to be dominant.66 Many HLA disease associations have been described. However, in most cases the HLA allele is associated with predisposition to disease, not with protection, and the reason for the association is not clear. The association of HLA-A*02 with protection from HAM/TSP is, by contrast, the only clear example of protection against any viral disease by a single class I HLA gene; and the reason for the association—efficient CTL surveillance against the virus—immediately suggests itself. The protective effect of HLA-A*02 also has direct implications for vaccination against both HIV-1ref1, Bangham CRM, 1613-17 and HTLV-1ref: it implies that an effective antiretroviral vaccine will elicit a strong and persistent CTL response to the virus.
        Transmission :
        • mucosal (colostral) route => APC infection => low level viral gene expresssion and no immune response elicited => adult T cells leukemia / lymphoma (ATL)ref : CD4+ leukemia in 1-5% of infected people within 20-30 years. Epidemiological studies have demonstrated that the relative percentage of malignant lymphoid proliferations varies widely according to geographical location and ethnic populations. ATL is incidentally associated with mother-to-child infection which occurs mainly through breast-feeding, elevated levels of proviral load, and insufficiency in HTLV-I-specific CTL responses. Among these, anti-tumor potentials of HTLV-I-specific CTL have been shown in ex vivo analysis of human HTLV-I-infected individuals and also in vivo experiments by using rat models of HTLV-I-infected lymphomas. In another rat model of HTLV-I-infection, orally infected rats showed significantly higher HTLV-I proviral load but lower HTLV-I-specific cellular immune responses than in intraperitoneally infected rats. As a result, persistent viral load was inversely correlated with levels of virus-specific T-cell responses. HTLV-I-specific T-cell responses in orally infected rats recovered by re-immunization. Conversion of Tax-specific T-cell responses from low to high levels was also observed in an ATL patient who obtained complete remission after hematopoietic stem cell transplantation. These findings suggest that HTLV-I-specific immune unresponsiveness associated with oral HTLV-I infection may be a potential risk factor for development of ATL, allowing expansion of the infected cell reservoir in vivo, and that immunological strategies targeting Tax may potentially reduce the risk of ATL and induce therapeutic effects on ATLref. Recent findings on the anti-tumor effects of Tax-targeted vaccination in rats and the reactivation of Tax-specific T cells in ATL patients as a result of hematopoietic stem cell transplantation imply promising immunological approaches for the prophylaxis and therapy of ATLref. This low incidence and the long latency period preceding occurrence of the disease suggest that additional factors are involved in development of ATLL. vDNA is clonally integrated in a latent state or defective => no v-protein is required for lymphomagenesis ? HTLV-induced malignancies are difficult to treat with conventional chemotherapy, and disease progression is often rapid with a median survival < 2 yearsref. After initial infection, HTLV-1 remains clinically latent for many years at low provirus copy numbers in CD4+ T cells. Once immune surveillance deteriorates and viral replication progresses, provirus copy numbers increase rapidly. Unlike other virus infections, apoptotic death of virus-infected "atypical" lymphocytes decreases with increasing viral load, thus favoring continued proliferation of these cells and further virus replication at the same time. Changes in the peripheral blood are characterized by coincident rises in oligoclonal lymphocyte populations including HTLV-1-positive CD4+ T-lymphocytes and their precursors with a progressive shift to immature cells as disease progressesref. HTLV-I is also associated with cutaneous T-cell lymphoma (CTCL)ref and T-LGL leukemia : however, a definite role of HTLV-I in mycosis fungoides (MF) and/or Sezary syndrome (SS) remains controversialref.
        • haematogenous route
          • sexual route in adults (male to female transmission is about four times as frequent as female to male transmissionref)
          • transplacental route
          • infected blood products has been a major problem in endemic regions, especially in Japanref1, ref2. Blood for transfusion is now screened routinely for HTLV-1 in several countries, including Japan, the USA, and Brazil. In Japan, screening of blood products and counselling on breast feeding has been followed by the beginning of a downward trend in the age dependent seroprevalence of HTLV-1ref1, ref2.
          => CD4+/CD8+ T cell infection => high level viral gene expression, bone marrow invasion, and strong immune response elicited => tropical spastic paraparesis (TSP) / HTLV-1 associated myelopathy (HAM) / chronic progressive myelopathy in 2-5 % of infected people.
        ATL-TSP coexistence is rare.
        => multiple sclerosis (MS) (?)
        => HTLV-1-associated bronchiolitis might be associated with conditions that are distinct from those of diffuse panbronchiolitis based on the different responses to macrolide treatment and the difference in the number of activated T cells bearing IL-2R in the lungsref.
        Laboratory examinations : the diagnosis of HTLV-1 infection is based on the detection of specific antibodies by particle agglutination or enzyme linked immunosorbent assays, and subsequent confirmation either by the polymerase chain reaction (PCR) or western blot assaysref. The most specific serological assay is the western blot, in which the antigen is a mixture of whole virus lysate with recombinant viral envelope proteins from either HTLV-1 or the closely related virus HTLV-2, which has not been convincingly associated with disease. The identity of the virus can be confirmed by PCR (Heredia A, 85–92); PCR is especially useful in cases where the western blot is indeterminate.
        Experimental animal models : after prolonged latency periods, transgenic mice developed diffuse large-cell lymphomas and leukemia with clinical, pathological and immunological features characteristic of acute ATLL. Transgenic mice were functionally immunocompromised and they developed opportunistic infections. Fulminant disease also developed rapidly in SCID mice after engraftment of lymphomatous cells from transgenic mice. Flow cytometry showed that the cells were CD4- and CD8-, but CD44+, CD25+ and cytoplasmic CD3+. This phenotype is indicative of a thymus-derived pre–T-cell phenotype, and disease development was associated with the constitutive activation of NF-kB. This model accurately reproduces human disease and will provide a tool for analysis of the molecular events in transformation and for the development of new therapeuticsref.
      • simian T-lymphotropic virus 1
    • primate T-lymphotropic virus 2
    • primate T-lymphotropic virus 3
      • human T-lymphotropic virus type 3 (HTLV-3) was discovered first in Cameroon in 2005 in a hunter who had handled or eaten bush meat (monkeys or apes hunted for food)ref
      • simian T-lymphotropic virus 3
    • human T-lymphotropic virus type 4 (HTLV-4), a virus distinct from all previously known human or simian T-lymphotropic viruses, was first discovered in Cameroon in Feb 2005 in a hunter who had handled or eaten bush meat (monkeys or apes hunted for food) : it's totally new, so we don't know any other simian virus that is related to itref
    • Researchers examined blood samples from 930 Cameroonians who handled or eaten bush meat (monkeys or apes hunted for food) using antibody screening and genetic analysis : they find that at least 6 different simian retroviruses had infected 13 of the people. 2 hunters were infected with 2 previously unknown HTLV viruses. They could be more widespread than we think they are. Up to 25 million people globally are infected with HTLV-1 and 2. Currently, specialized tests are needed to find the viruses. After infecting one person, simian viruses often spread from person to person through sex, mother-to-child transmission, and other exchanges of blood and body fluids. Like HIV, the incubation period for HTLV viruses to cause disease can last decades.
  • Gammaretrovirus
    • Mammalian virus group
      • Replication competent viruses
        • murine leukemia virus (MLV) : causes leukemia and solid tumors in rats, mice, hamsters, and other animals; the genus includes the
          • Friend murine leukemia virus (F-MuLV) : => erythroleukemia
          • Moloney murine leukemia virus (M-MuLV / MoMLV / MoMuLV) : => lymphoid leukemia

            • All retroviruses specifically package 2 copies of their genomes during virus assembly, a requirement for strand-transfer-mediated recombination during reverse transcription. Genomic RNA exists in virions as dimers, and the overlap of RNA elements that promote dimerization and encapsidation suggests that these processes may be coupled. Both processes are mediated by the nucleocapsid domain (NC) of the retroviral Gag polyprotein. Dimerization-induced register shifts in base pairing within the y-RNA packaging signal of MoMuLV expose conserved UCUG elements that bind NC with high affinity (dissociation constant = 75 x 12 nM). These elements are base-paired and do not bind NC in the monomeric RNA. The structure of the NC complex with a 101-nucleotide 'core encapsidation' segment of the MoMuLV y site reveals a network of interactions that promote sequence- and structure-specific binding by NC's single CCHC zinc knuckle. Fndings support a structural RNA switch mechanism for genome encapsidation, in which protein binding sites are sequestered by base pairing in the monomeric RNA and become exposed upon dimerization to promote packaging of a diploid genomeref.
          • unclassified Murine leukemia virus
            • Rauscher murine leukemia virus
  • Lentivirus
  • Primate lentivirus group
  • Spumavirus is so-called because unlike other retroviruses it causes cells to form syncytia and look, on a slide, like foamy bubbles. Spumaviruses are harboured by domestic cats, cattle, and other animals in close contact with humans, but have not been associated so far with any disease state in any host. These viruses appear to be ubiquitous in all nonhuman primates, but only to be present in humans as rare zoonotic transmissions as described in the above report. The replication of foamy viruses differs from the standard retrovirus pattern in several important respects, and this sets the spumaviruses apart from the more familiar oncogenic and immunodeficiency retroviruses. In particular, there are 2 transcription start sites in the larger size of their genome, the polymerase (transcriptase) protein is expressed from a spliced subgenomic mRNA, and reverse-transcribed DNA is present in large amount in the extracellular virion. Infection of natural hosts by spumaviruses leads to a lifelong persistent infection, without any evidence of pathology. In general there is no epidemiological evidence of spumavirus pathogenicity in natural, experimental, or zoonotic infections. However, whether cross-species transmission (either by contact with primates in the wild or consumption of bushmeat) will alter the apathogenic nature of spumavirus infection remains an open question. No oncogene-containing member of the genus has been found. Foamy viruses are widespread, and exogenous viruses are found in many animals. A feline foamy virus (formerly known as feline syncytium-forming virus) is perhaps the easiest virus to isolate from domestic cats in view of the characteristic rapid cytopathic effectref.
  • Human foamy virus (HFV)
    • => apparent lack of associated disease
  • simian foamy virus (SFV)
    • Epidemiology : SFV or spumaretrovirus is transmitted at a higher rate (about 2-5%) than other primate retroviruses to zoo workers and research workers. SFV is also endemic in 70-90% Old World primates, such as chimpanzees and macaques, born in captivity, whereas the the New World monkeys, which are normally kept as pets, are not known to transmit the virus.. For these reasons, SFV infection can serve as a sensitive marker for the potential for natural infection with other, less transmissible simian retroviruses, such as SIV. Furthermore, SFV is genetically diverse and shows host-specific viral lineages, which facilitate the identification of the non-human primate source species in SFV-infected people.
    • SFV infection was confirmed in a worker, occupationally exposed to nonhuman primates, who donated blood after the retrospectively documented date of infection. Recipients of blood from this donor were identified and blood samples from such recipients were tested for SFV infection by Western blot and PCR assay. 1 recipient of RBCs and another recipient of FFP had died; retroviral infections were not implicated. 1 platelet recipient could not be tested. Recipients of RBCs (2), a WBC-reduced RBC unit (1), and a platelet unit (1) tested SFV-negative 19 months to 7 years after transfusion. Tested recipients had transfusions 3 to 35 days after blood donation. Samples of one lot of albumin and 3 lots of plasma protein fraction (manufactured from recovered plasma from two donations) tested negative both for antibodies and for viral RNA. The conclusion was that SFV transmission through transfusion was not identified among 4 recipients of cellular blood components from one SFV-infected donor. Derivatives containing plasma from that donor tested negative for SFVref
    • Cameroon : 10 of nearly 1,100 people from 9 separate rural villages saying that they had had some contact with monkey and ape blood through hunting and butchering them carried antibodies to SFV in their blood, suggesting they had been exposed to it due to hunting and butchering of bushmeat. And at least 3 people who came from different villages in the lowland forest of southern Cameroon picked up the virus from 3 separate animals - Gorilla gorilla, Mandrillus sphinx, and Cercopithecus neglectus - 2 of which (De Brazza's guenon and mandrill) are naturally infected with SIV. One of the 3, a 45-year-old man, said that he butchered and ate monkey, chimpanzee, and gorilla and regularly hunted them using guns, bows, and wire snares. The other 2, a 48-year-old woman and a 25-year-old man, told similar stories. None appeared unwellref. In 1998, Walid Heneine and colleagues at the US Centres for Disease Control and Prevention in Atlanta tested the blood of 231 lab workers who handled monkeys and found that 4 had become infected with SFV (evidence of SFV infection included seropositivity, proviral DNA detection, and isolation of syncytium-producing virus) : one man had been infected for 20 years and another for 9 without apparent damage
    • Bali, Indonesia : the transmission of the virus from a monkey to a human took place at a monkey temple. Even though this particular virus jumping to humans may not prove dangerous, the dense human and primate populations in Asia could lead to other primate-borne viruses jumping the species barrier and causing human disease. The issue of primate-to-human viral transmission has been studied extensively in Africa, largely because that is where HIV originated, but there has not been much work on the topic in Asia, which has huge primate diversity and large human populations. The vast majority of previous viral transmission research focused on bushmeat hunting and consumption, a practice in which local residents hunt monkeys for food [more commonly practised in Africa]. HIV, the virus that causes AIDS in humans, is believed to have originated as simian immunodeficiency virus (SIV), and jumped the species barrier to humans when African bushmeat hunters came into contact with blood from infected animals. Though bushmeat hunting and consumption may be a significant factor in viral transmission in Africa, people in Asia have many other contexts in which they come into contact with primates, including animal markets, primate pet ownership, urban performing primates, and zoos. In addition, monkeys are significant symbols in both Buddhism and Hinduism, and monkey temples -- places of religious worship that have become refuges for populations of primates -- are common throughout much of South and Southeast Asia. In these areas, protected macaque populations have thrived alongside dense human settlement for centuries. On the island of Bali alone, there are > 40 such temples, which are frequented by tourists from around the world. About 700,000 international tourists visit the island's 4 main monkey temples every year. Temple workers and people who live near the temples also have a great deal of contact with monkeys at the religious sites. In Asia, the amount of contact between humans and primates in temple settings dwarfs the contact due to bushmeat hunting,. For this study, the researchers tested blood samples from 82 people who work in or around a temple in Bali, as well as samples from macaques in the area. They found antibodies for simian foamy virus in the blood of one 47 year old farmer who visited the temple every day. They confirmed the tests by performing a DNA analysis of the man's blood and found that the SFV strain he carried was the same strain found in the temple's macaques. The man denied owning a monkey as a pet, or hunting monkeys for food. He had been bitten once and scratched more than once by the temple's macaques. Researchers still don't know the long-term effects of SFV on humans. There are about 40 known cases of people being infected through laboratory or zoo contact or through bushmeat hunting in Africa. There are no known cases of human disease yet. However, there are other primate viruses known to be harmful that could jump the species barrier. They don't want people to be afraid of coming in contact with macaques or other primates, but they do urge people to be cautious and careful when interacting with monkeys. Feeding the animals, or even carrying food into a temple, can greatly increase the risk of a bite or scratch, which can lead to transmission of infection. Visitors occasionally engage in other risky behavior, such as touching animals or trying to hold baby monkeys. Limiting such behavior can reduce the risk of bites and scratches. If you look at free-ranging monkeys in Singapore's nature reserves, you see that feeding by visitors is not allowed, and it is actively discouraged. Interspecies interaction there is very different, and rates of human-monkey contact are much lower. Limiting dangerous contact between primates and humans can have other benefits as well, such as reducing the transmission of human infections to monkeys. Human measles, for instance, can cause disease in monkeys and can even kill them. Other primate species have already seen significant population losses because of infection by human illnesses. The 1st reported transmission to a human of SFV from a free-ranging population of nonhuman primates in Asia was so described. The transmission of SFV from macaques (Macaca fascicularis) to a human at a monkey temple in Bali, Indonesia was investigated with molecular and serologic techniques. Antibodies to SFV were detected by Western blotting of serum from one of 82 humans tested. SFV DNA was detected by nested polymerase chain reaction (PCR) from the blood of the same person. Cloning and sequencing of PCR products confirmed the virus's close phylogenetic relationship to SFV isolated from macaques at the same temple. This study raises concerns that persons who work at or live around monkey temples are at risk for infection with SFVref.
    => so far, no unambiguous evidence of illness has been associated with enzootic infection of humans with SFV
  • Human spumaretrovirus
    • => chronic fatigue syndrome (CFS) (?)
    Laboratory examinations : Bibliography Generalities for viroses Web resources
    Copyright © 2001-2012 Daniele Focosi. All rights reserved  |  Terms of use  | Legal notices
    About this site  |  Site map  |  Acknowledgements |    |  Current link partners
     Abbreviations and acronyms  |  Medical terminology  |  Add a link  |  Translate this site into your favourite language  |  Softwares |  Cite this page!

    This website subscribes to the HONcode principles of the HON Foundation. Click to verify.
    PicoSearch
     
    Search 



    Search
    for 


    Search Medical Dictionary 
    for 
    fmer