PRIMATE LENTIVIRUS GROUP : they all use CD4 as receptor (hence infect CD4⁺ T_h lymphocytes) and have a conic core which undergoes maturation after budding.

Table of contents :

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HIV-1 Epidemiology Genomics Proteomics Transmission Pathogenesis Symptoms & signs Laboratory examinations Therapy Prevention Experimental animal models

HIV-2 Epidemiology Proteomics SIV Epidemiology Proteomics Transmission Pathogenesis Therapy Web resources News

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• Human immunodeficiency virus
• Human immunodeficiency virus type 1 (HIV-1) / human T-cell lymphotropic virus type III (HTLV-III) / lymphadenopathy virus (LAV)
Epidemiology :
• history :
• arose from SIV and moved into humans around 1930 by butchering chimpanzees (Pan spp.) for bushmeat in West-Central Africa. Apes are traditionally hunted in Africa and are offered for sale in open-air meat markets. The bloody carcasses are regularly covered with blood-feeding flies, amongst them possibly the stable or biting house fly (Stomoxys calcitrans), a cosmopolitically occurring biting fly. This fly is the effective vector for the retrovirus causing equine infectious anemia. According to laboratory experiments, the infectivity of ingested HIV is not reduced in the regurgitates of this fly.
• arrived in the USA around 1968
• one hypothesis suggests that Canadian air steward Gaetan Dugas - dubbed Patient Zero - brought in the disease and spread it to many homosexual partners
• according to a recent study the disease entered many different times independently. Even early in the epidemic the viruses in different cities were distinct from one another. This supports another popular theory: that HIV may have hitched a ride with tourists arriving from Haiti^ref
• epidemic in 1974 near Lake Victoria (Kinshasa, Zaire)
• retrospectively recognized as having struck in the late 1970s
• first reported in 1981 : this is compatible with HIV's roughly 10-year incubation period. It was discovered by an epidemiological research that showed increase in sales of pentamidine chlorhydrate in New York and San Francisco districts : the drug was used to treat opportunistic Pneumocystis carinii infections (see below).
• prevalence : 42 million people at November 2002, 38 million people in 2003. In 2003, nearly 50% of all people infected between the ages of 15 and 49 are women. In Africa, the proportion is almost 60%. In 2004 nearly 50% of the estimated 39.4 million people living with HIV, the virus that causes AIDS, are women and girls, whether married or single, promiscuous or faithful. The trend is that more young women are being infected than young men : if they are married, they can't abstain. They are faithful but the husband is not faithful. Women need information, including how to use a female condom to protect themselves. Men and women between 15 and 24 years old are the hardest hit by the pandemic
• Asia (with 60% of the world's population) : 7.4 million people in 2003. An estimated 10 million people will carry the virus by 2010 unless effective action is taken
• India : 5.1 million infected individuals (0.9%) in 2003. According to the CIA, the number of cases in India could top 20 million by 2010. The people hit by AIDS in India are not the ones you would expect. About 86% of cases are a result of sexual transmission, most of it heterosexual. Intravenous drug use accounts for only 2.4% of infections, except in Nagaland and Manipur, 2 states where HIV infection is highly prevalent. The earliest cases appeared in high-risk groups: among the country's 3 million sex workers or the 5 million truckers who haul the virus up and down the highways. During 2004, there were just 28,000 new cases of HIV infection, down 95% from the previous year — proof that its strategies are working. But even in the United States there are an estimated 40,000 new cases each year. So do you believe that Indian number? Of course not, that would be ridiculous. Compared with South Africa, where the prevalence of HIV is 21.5%, India's prevalence is just 0.91%. That is < 1% generally considered to be the tipping point, beyond which the epidemic will escalate out of control. It took just 7 years for South Africa's prevalence to rise from 1% to 20%. But the statistics are sobering. 6 states in India already have a prevalence > 1%, and in 2004 the number of high-prevalence districts jumped from 49 to 116. Even in the low-prevalence or 'highly vulnerable' states, as they are now dubbed, there are pockets where > 4% of adults are infected. Over the next 5 years, it plans to expand its 670 voluntary testing sites to 24,000 and increase the number of people on antiretroviral therapy from an estimated 8,000 to 188,000. But in the world's most populous democracy, good intentions don't go very far. Despite doubling its AIDS budget since 2003-04, India still only spends about 29 US cents per person on AIDS. In contrast, Uganda, credited with curbing its AIDS crisis, dedicates US$1.85 per person. Already, India accounts for > 13% of the world's AIDS burden but with its prevalence so close to the tipping point. In Mumbai, the bustling metropolis on India's west coast, there are nearly 100,000 sex workers. Volunteers from non-governmental organizations (NGOs) walk through the streets of Kamathipura, the red-light district, handing out condoms and leaflets. But in the southern states, where prevalence is highest, there are no red-light districts to canvass. Instead, sex workers — many of whom are married women — work out of their homes, hotels or on the highways, earning themselves the nickname 'highway queens'. Some towns, such as Peddapuram and Amalapuram in the state of Andhra Pradesh, are like one big red-light district. For US$230, you can stay there for 1 month and be treated like a mappillai, a son-in-law, who is treated like a prince by the girl's family. In Andhra Pradesh, HIV prevalence jumped from 1.25% in 2003 to 2.25% in 2004. Experience has shown that the best way to reach these unconventional sex workers is through their peers. There are 638,000 villages in India, many of them with bad roads, no running water and no medical care. The best estimates are that 59% of those infected with HIV live in rural areas, but because there is limited surveillance there, the real number is likely to be higher. Compounded by ignorance and illiteracy, myriad myths about AIDS have taken root: that eating chicken and brinjal (aubergine) is harmful, for example, or that the virus can be transmitted by mosquito bites. Some largely rural states such as Uttar Pradesh and Bihar have all the ingredients for a massive epidemic — illiteracy, poverty, migrant labour and sex traffic — but have so far received little attention either from the government or from donor agencies. The model of success for those states is perhaps Tamil Nadu, where the epidemic spawned dozens of NGOs that conduct education programmes and provide counselling and support. As a result, it is the only state where prevalence has dropped — from 1.13% in 2001 to 0.63% at the last count.  Truckers go home only once every few months. On the road, they have multiple sexual partners and often abuse drugs and alcohol. Many believe that if they don't have sex they will build up garmi, a Hindi word meaning heat, and will go blind. In recent years, they've become accustomed to being chased by volunteers with flipcharts and penis models in their pockets. Selvaraj works with the HOPE Foundation, which has counsellors and doctors at several stops along a 60-km stretch on the highway. But the message has not entirely got through. Believing that AIDS can only be transmitted by women, many truckers now have sex with 'cleaners', the young boys who travel with them. Homosexuality is illegal in India, so the government's campaigns mostly neglect men who have sex with men. These truckers have ample access to condoms, but many use the condoms to plug pipes in the trucks. According to a report by India's comptroller and auditor-general, 75% of the 1.5 billion condoms made each year are used as sealants for leaky roofs, as lubricants in weaving gold-embroidered saris, or are mixed with concrete and tar to pave roads.
• China : 840,000 HIV-positive people and 80,000 with full-blown AIDS. In the mid-1990s, the Chinese government established a system of centres to screen donated blood and its products for HIV. But the low cost and ready availability of unregulated rural samples kept demand high, and contaminated blood continued to slip through the net. In some provinces, including Anhui, Henan and Shandong, the disease took off in the early 1990s when poor farmers began selling their blood plasma. Without clean needles the disease spread, and in some villages up to 60% of people are now infected. 3 new laws, passed at the 11th session of the Standing Committee of the National People's Congress, builds on earlier regulations governing blood safety and made it illegal to buy and sell blood and discriminate against victims of infectious diseases, and guarantee funds for preventing infectious disease. China passed a law in August 2004 to make it illegal to buy and sell blood in an effort to stem the country's growing AIDS epidemic, the first time the disease has been targeted in a law. Officialsof relevant United Nations organizations warned that the number could hit 10 million if the epidemic goes unchecked. As part of the measures to curb the disease, China has made AIDS prevention a compulsory course of schools ranging from junior high schools to colleges. China also launched pilot clinics last year to provide methadone maintenance therapy to intravenous drug users and programs to promote the use of condoms at hotels, universities and nightclubs. Shanxi Province in North China will conduct HIV testing among people who have sold blood since 1990 during the first 4 months of 2005. A senior official at the department said that some people infected with the HIV virus have yet to be traced after the blood-sale scandal. The department also requested local health bureaus to conduct antibody testing on the spouses and children of previous blood sellers who were found HIV positive and to offer timely anti-retroviral treatment to the patients. To prevent possible discrimination, the department asked health institutions to protect HIV carriers' privacy and keep the testingresults secret.
• > 1.5 million people are now HIV⁺ in eastern Europe and central Asia, compared with just 30 000 in 1995. > 1 in 100 people in Estonia, Russia, and Ukraine are infected with the virus : the result could see the annual growth in gross domestic product reduced by 1%. Just as in some CIS countries today, only 12 years ago South Africa too saw < 1% of its adult population infected--now that rate is 20 times higher. Lessons can be learned from successes in countries such as Poland, the Czech Republic, and Slovakia. Currently only 7000 people in eastern Europe and central Asia receive antiretroviral therapy for HIV--9% of those who need the drugs in the region
• some 27 companies in Asia make generic versions of patented antiretroviral medications. But of 1.3 million Asians who need the drugs, only 7% have access to them, the report states. Computer models predict that HIV will spread most rapidly in countries where > 20% of men visit sex workers : Thailand, which saw an early and rapid rise in infections in the late 1980s, increased condom use among Thai sex-workers to nearly 90% and halved the number of men who visited them. As a result, the number of new people testing positive for HIV in the country fell from 142,819 in 1991 to 21,260 this year.
• Africa : 7 countries in southern Africa report prevalence rates > 15%. They are Botswana, Swaziland, Lesotho, Zimbabwe, South Africa, Namibia, and Zambia (a prevalence rate > 1% is considered to be a generalized epidemic)
• South Africa : the world's largest number of HIV-positive people – 5.3 million people (18%). 20% of people aged 15-49 are infected
• Botswana : 38.8% of adult population is infected (the world highest rate)
• Tanzania : 10% of population
• Uganda : there are 70% fewer cases of HIV in 2004 compared with 10 years ago (500,000 Ugandans are HIV positive in 2004, compared with 1.5 million a decade ago) because there is 60% less casual sex. In 1984, when infection was at its peak, billboards, radio shows and concerts shouted a coordinated anti-HIV message. Public figures, including politicians, religious leaders and health workers, promoted safe sex and people began to use condoms more often. But similar strategies in other African countries did little to lower the prevalence of HIV. The difference is that in Uganda people became engaged with the epidemic at the community level : local care groups, religious movements, non-governmental organisations and care networks all spread the message. Families, friends and neighbours began talking about HIV prevention and care, and sexually transmitted diseases stopped being a taboo topic. The issue also became personal : most people now know someone who has AIDS or has died from the disease and this has motivated people to change their behaviour. The situation echoes San Francisco in the late 80's when HIV had a stranglehold on the gay community : the best predictor of behavioural change back then was knowing someone with HIV or AIDS.
• USA : between 1,039,000 and 1,185,000 people were living with HIV in December 2003; 40,000 new cases a year. The previous estimate from 2002 showed that between 850,000 and 950,000 people had the AIDS virus. The jump reflects the role of medicines that have allowed people infected with the virus to live longer. Of those, almost 25% are unaware of their infection, and 400,000 have full blown AIDS. For the first 2 decades of the AIDS epidemic in the USA, HIV-1 subtype B has been the predominant isolate throughout the country. In recent years, non-B HIV-1 subtypes have been spreading in parts of Europe. In 2003, the Minnesota Department of Health piloted HIV-1 subtyping with routine surveillance to describe and monitor non-B-subtype HIV-1 isolates. In Minnesota, African-born persons make up < 1% of the population, but in 2002 accounted for 21% of the state’s new cases of HIV infection. All of those infected with non-B subtypes were African immigrants attending health clinics in the Minneapolis-St. Paul area. Of the 98 African-born HIV-1-infected patients, 87 were successfully subtyped and 95% of these were infected with non-B subtypes. 7 different subtypes were identified, all consistent with strains endemic to the patients’ regions of birth. Of the non-African HIV-1-infected patients, 25 were successfully subtyped and all were infected with subtype B. These results underestimate the prevalence of non-B subtypes in Minnesota because recent immigrants are less likely than assimilated immigrants to have access to the American health care system. Since their estimates are based solely on patients from health care facilities, they probably missed recent immigrants with HIV infection.  The findings of a high prevalence of non-B subtypes in a state where African-born individuals make up < 1% of the population suggest that it may be time to consider implementing HIV subtype surveillance in states with larger immigrant populations and throughout the USA. In the 1990s, the CDC and other agencies generally agreed that between 600,000 and 900,000 people had the virus, according to the University of California-San Francisco's Center for HIV Information. Previous estimates -- as high as 1.5 million people -- from the 1980s were later determined to be too high. For example, the CDC estimated in 1986 that between 1 million and 1.5 million people had HIV. In 1987, that was revised to 945,000 to 1.4 million and was refined in 1990 to 800,000 to 1.2 million. The CDC's latest estimates indicate blacks account for 47% of HIV cases; gay and bisexual men make up 45% of those living with the virus that causes AIDS, the health agency believes. In 2003, the rates of AIDS cases were 58 per 100,000 in the black population, 10 per 100,000 Hispanics, 6 per 100,000 whites, 8 per 100,000 American Indian/Alaska native population, and 4 per 100,000 Asian/Pacific Islanders. The CDC also warned those demographics may soon change because heterosexual blacks, women and others infected after having high-risk sex (such as with someone with HIV, an injection-drug user or a man who has sex with other men) now account for a larger proportion of those living with HIV than those who are living with full-blown AIDS. Of 156,000 new cases of HIV infection between 2001 and 2004, 51% were in non-Hispanic blacks — although blacks made up just 13% of the population in those states : the rate of HIV diagnosis fell by 6.8% annually among black women and 4.4% annually among black men between 2001 and 2004. The HIV diagnosis rate even fell by 9.7% every year on average among black male users of injected drugs. 32% of black men in Baltimore who had sex with other men, which includes homosexual and bisexual activity, were infected with HIV
• Brazil : the nation of about 170 million slashed Aids deaths to 24,8% of the infected population in 1999 from 73,7% in 1990. In absolute numbers, Latin America's largest country suffers from a high rate of HIV infection, with 200,000 registered cases of HIV, and estimates of up to 540,000 total cases. But only 0,6% of the adult population is infected. Currently, there are almost 600,000 HIV-infected individuals in Brazil. From 1984 to 2004, 362,364 AIDS cases were officially reported and 155,000 patients are under HAART treatment^ref
• Kazakhstan : of 10 175 children at risk in Shymkent, South oblast, 9032 children (88.8%) were screened for HIV infection in 2006, which was confirmed in 100 children and in 7 mothers. 6 children among those infected have died, and one has been adopted and left Kazakhstan^{ref1, ref2}.
• incidence : 4.9 millions in 2004, 4.8 millions in 2003 (25% is Asian; 3 million people in sub-Saharan Africa)
• there will be 45 million new infections by 2010
• India : in 2003 there were 520,000 new cases of HIV infection, 28,000 in 2004 (???), but 2 of India's most populous states -- Uttar Pradesh and Bihar with a combined population of > 250 million -- had poor surveillance. This is 85% of the 2002 figure of 610,000 new infections.
• Thailand : in 2003, 21,000 people became infected, compared with 140,000 people in 1996; an increase in condom use and a decrease in the sex trade have contributed to the trend^ref
• UK : there has been a 20% increase in new diagnoses of HIV infection between 2002 and 2003 : new diagnoses in heterosexuals have risen by 27% in the same period, with most infections contracted outside of the UK in countries with a high rate of infection with HIV. The increase in rates is also though to be related to an increase in other STD, which might influence the transmission of HIV
• USA : 40,000 new HIV infections have occurred every year since the 1990s. However, recent outbreaks of HIV and sexually transmitted diseases in major cities around the country offer a hint that new infections may be as high as 60,000 cases a year
• mortality : 3.1 millions in 2004
• there will be nearly 70 million deaths from the disease by 2010
Genomics : viral genome transcription initially depends on NFkB, generating a double-spliced 2 kb transcript. LPS stimulation of TLR4induces TIRAP and MyD88 activation => RAC1 activation and RAC1 stimulates trans-activation of the HIV long-terminal repeat (HIV-LTR)^ref. Although HIV-1 infects quiescent and proliferating CD4⁺ lymphocytes, the virus replicates poorly in resting T cells : in the latter MURR1 inhibits HIV-1 growth in part through its ability to inhibit basal and cytokine-stimulated NFkB activity^ref
Strains from A to I exist (3 subgroups (M, N, and O)) : A/E mosaic is the most virulent strain. Biological phenotype may be classified according to  ..
• syncitium-inducing capacity in MT-2 cells (which express CXCR4 / CD184 / fusin / LESTR but not CCR5 / CD195) :
• non-syncitia-inducing (NSI) strains are usually those which are acquired in infection.
• syncitia-inducing (SI) strains are more virulent and usually develop at the end of the disease : anyway when cotransmitted together with NSI strains, they worse the prognosis. They are characterized by amino acid substitutions in codons 11 (?=>Arg) and 25 (Gly=>?) within V3 loop of env.
• env sequence => coreceptor usage => cell tropism :
• macrophage-tropic (M-tropic) / non-T-cell-line-tropic / R5 strains infect macrophages and primary CD4⁺ T lymphocytes. They use CCR5 / CD195 as coreceptor. Proliferation kinetics in U937-2, CEM, MT-2 and Jurkat-tat cell lines is slow/low (S/L), with pattern 1, 2 or 3. In lymph nodes, CXCR4-bearing cells are found almost exclusively inside GCs and in the medulla. Early after infection preferential entry and replication of R5 HIV-1 was predominantly detected in mature CD3^+/hiCD27⁺ thymocytes, although 5.3% of HIV-1 infected immature thymocytes express R5 HIV-1 indicating potentially latent, viral DNA can be established early in T cell development.. Thus, R5 HIV-1 targets the stage of development where thymocytes acquire functional responsiveness which has important implications for HIV pathogenesis^ref
• T-cell-line-tropic (T-tropic) / X4 strains infect macrophage and CD4⁺ T lymphocytes. They mainly use CXCR4 / CD184 / fusin / LESTR as coreceptor, but can also use CCR5 / CD195, CCR3 and CCR2B. Proliferation kinetics in U937-2, CEM, MT-2 and Jurkat-tat cell lines is rapid/high (R/H). In lymph nodes, CCR5-bearing cells exist primarily in the medulla and extrafollicular areas of the cortex, surrounding the FDC reservoir of infectious virus : FDC themselves upregulate CXCR4 expression. X4 HIV-1 expression and replication were primarily found in immature CD3^-/+/lowCD27^-CD69^- thymocyte^ref
• dual-tropic / R5X4 strains use CXCR4 / CD184 / fusin / LESTR, CCR5 / CD195 and CCR2B as coreceptors
Although in vitro studies have identified HIV-1 strains that can use other co-receptors, infection of human cervical tissue using co-receptors other than CXCR4 or CCR5 is unlikely. In contrast to infection of cervical tissue, uptake of HIV-1 by migratory DCs is not inhibited by a combination of CXCR4 and CCR5 inhibitors, but is inhibited when CD4-specific antibodies and mannan are present. Presence of DC-SIGN-specific antibody also inhibit the capture of infectious virus by migratory cells, albeit to a lesser extent, indicating an important but not exclusive role for this receptor in virus capture and transmission. By targeting HIV-1 directly with neutralizing gp120-specific antibodies and a CD4-Ig fusion protein, both localized infection of cervical tissue and transfer of infectious virus by migratory cells are inhibited^ref.
Resulting phenotypes may be :
• common variants :
• S/L M-tropic NSI
• R/H T-tropic SI
• rare variants :
• S/L SI
• R/H NSI
Lentiviral strains capable of only one round of infection in vitro and in vivo to investigate the dynamics and pathogenesis of HIV and SIV have been created by mutating the ribosomal frameshifting site between the gag and pol reading frames^ref.
Proteomics :
• Env / gp160 / transmembrane (TM) envelope gp
• gp120 : 3 molecules of gp120 are non-covalently linked to trimeric gp41, forming heteroligomeric spikes on the surface of the virus particle. Different regions of gp120 interact with CD4 and chemokine receptors found on the surface of target cells. These interactions lead to a series of conformational changes in gp120, and subsequently allow the conformational changes in gp41 that lead to formation of the coiled-coil form and exposure of the fusion peptide
• CD4-binding domain (CD4bd) : composed of several parts of the gp120 molecule, forming a binding pocket into which a region of CD4 fits
• bridging sheet : composed of 4 anti-parallel b strands from the V1/V2 stem and the C4 regions of gp120. This region is involved in the binding of gp120 to chemokine receptors, triggering subsequent conformational changes in gp120 and gp41. Because this region forms or is exposed after binding of gp120 to CD4, it is known as the "CD4-induced epitope".
• V2 loop : a highly variable region that is proximal to the CD4bd and is part of the bridging sheet. The V2 loop (together with the V1 loop) seems to shield partially the CD4bd, the bridging sheet and part of the V3 loop until conformational changes in gp120 are induced by CD4.
• V3 loop : a semi-conserved region of gp120 that is structurally constrained by its requisite participation in virus infectivity. The V3 loop interacts with chemokine receptors on the sruface of target cells.
It also binds to CD209 / dendritic-cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) / CIRE, macrophage mannose receptor and langerin on DCs. In primary immature DCs, internalized virus particles are rapidly degraded in and endo-lysosomal compartment. MHC class-I-restricted peptides are derived from a small number of virions that enter the cytosol (after membrane fusion) and are degraded by the proteasome, rather than from the majority of virions that are degraded in the endo-lysosomal compartment. Tight contact with permissive CD4⁺ T lymphoctes in antigen-independent structured immunological synapses allows infection of the latter, but DCs also induce IFN-g production by the CD8⁺ effector T cells and formation of high levels of antibodies whose neutralization ability is impaired by a receptor-binding site conformational masking mechanism. Cell contact between DCs and T cells in lymph nodes might make the transmission process so efficient that only small amounts of virus that avoid degradation are required. Alternatively, HIV-1 could replicate in DCs at low levels, so that progeny virions rather than captured virions could be transmitted to T cells^ref.
• gp41 transmembrane glycoprotein is found as a homotrimeric complex in the envelope of the viurs; it interacts non-covalently with gp120 on the exterior of the virus particle
• immunodominant region (includes gp41 epitope cluster I) : induces high levels of antibodies, most of which are not neutralizing but might mediate other functions, such as ADCC and aggregation of and complement deposition on virus particles
• transmembrane-proximal region : poorly exposed on the surface of the virus and is thought to be a transitional epitope, exposed for a brief period of time during the confromational changes that occur in gp41 that lead to the fusion of virus and cell membranes
• amino-terminal and carboxy-terminal heptad repeat regions: the repeating motifs in these regions form leucine zippers, which are involved in the formation of the coiled-coil form of gp41 after conformational changes are induced in gp120 by its interaction with CD4 and chemokine receptors
• fusion peptide : the amino-terminal region of gp41, which is exposed after formation of the coiled-coil form. This region is inserted into the membrane of the target cell, resulting in fusion of virus and cell membranes
Virions of wild-type HIV-1 and a mutant SIV had 14 and 73 spikes per particle, respectively, with some clustering of HIV-1 spikes. 3D averaging showed that the surface glycoprotein (gp120) 'head' of each subunit of the trimeric SIV spike contains a primary mass, with 2 secondary lobes. The transmembrane glycoprotein 'stalk' of each trimer is composed of 3 independent legs that project obliquely from the trimer head, tripod-like. Reconciling available atomic structures with the 3D whole spike density map yields insights into the orientation of Env spike structural elements and possible structural bases of their functions^ref.
• Gag / p2 / p6 / p55 / nucleocapsid (NU) / matrix (MA) : a 30-residue coiled-coil motif at the N-terminus is required for targeting free and structured capsids to the microtubule organizing center (MTOC)—or centrosome— via  dynein-dynactin retrograde microtubule motor (with Gag directly interacting with dynein light chain 8 prior to nuclear translocation of the viral genome. It intreracts with endophilin 1 and 2 (cytosolic proteins converting lysophosphatidic acid by addition of the fatty acid arachidonate into phosphatidic acid, involved in the formation of endocytic vesicles), which remain as minor components of virions : also a-adaptin) becomes included in the virion . Gag is sufficient to produce a virus-like particle, during which Gag is cleaved into four structural proteins :
• MA
• p12
• capsid protein (CA) : interaction of CA with the host cell protein cyclophilin A (CypA) prevents inhibition by the restriction factor REF1 / APEX nuclease (multifunctional DNA repair enzyme) 1 (APEX1). Alterations in protection upon maturation provide evidence for the maturation-induced formation of an interaction between the N- and C-terminal domains in half of the capsid molecules, indicating that only half of the capsid protein is assembled into the conical core^ref.
• NC
• Pol / protease / integrase (IN) / reverse transcriptase (RT) / p160. HIV-1 preferentially integrates into transcribed regions. Host p300 acetylates K264, K266, and K273 in the carboxy-terminus of IN, a region that is required for DNA binding, increasing IN affinity to DNA, and promoting the DNA strand transfer activity of the protein^ref
• accessory genes :
• Nef / p27 is found in virion and has NLS. Macrophages that express Nef or that are stimulated through the CD40 receptor release sCD23 and sICAM that render CD4⁺ T lymphocytes permissive to HIV-1 infection without progressing through the cell cycle. Then Nef triggers CD4 endocytosis preventing overinfection and signal tranduction. It interacts with the N3 subunit (impairing binding of PA28 but not of the 19S regulator) of the 26S proteasome. One action of Nef is to down-regulate surface MHC I molecules, helping infected cells to evade immunity. Nef also down-regulates the macrophage-expressed MHC-Ib protein HFE, which regulates iron homeostasis and is mutated in the iron-overloading disorder hemochromatosis. In model cell lines, Nef reroutes HFE to a perinuclear structure that overlaps the trans-Golgi network, causing a 90% reduction of surface HFE. This activity requires a Src-kinase-binding proline-rich domain of Nef and a conserved tyrosine-based motif in the cytoplasmic tail of HFE. HIV-1 infection of ex vivo macrophages similarly down-regulates naturally expressed surface HFE in a Nef-dependent manner. The effect of Nef expression on cellular iron was explored; iron and ferritin accumulation were increased in HIV-1-infected ex vivo macrophages expressing wild-type HFE, but this effect was lost with Nef-deleted HIV-1 or when infecting macrophages from hemochromatosis patients expressing mutated HFE. The iron accumulation in HIV-1-infected HFE-expressing macrophages was paralleled by an increase in cellular HIV-1-gag expression. Through Nef and HFE, HIV-1 directly regulates cellular iron metabolism, possibly benefiting viral growth^ref
• transcription activator (Tat) / p14 (86 and 101 amino acid isoforms in different strains) functions through binding to a short leader RNA, called transactivation responsive element (TAR) together with HIV TAT specific factor 1 (HTATSF1), a cofactor required for Tat activation of HIV-1 transcription. Within nucleus it activates the HIV-1 long terminal repeat (LTR), mainly by adapting co-activator complexes, such as p300/CBP, pCAF and the positive transcription elongation factor P-TEFb (cyclin T1 + CDK9), to the promoter, promoting phosphorylation of the CDD on RNA polymerase II. The protein-protein interface involves hydrophobic interactions between the P/CAF ZA loop and the Tat core domain. In particular, tyrosines 760 and 761 of P/CAF, 2 residues that are highly conserved in most known bromodomains, play an essential role for the binding^ref. The proto-oncoprotein Hdm2 interacts with Tat and mediates its ubiquitination enhancing Tat-mediated transactivation via a non-proteolytic function. Tat also interacts with the a-rings (impairing binding of PA28 but not of the 19S regulator) of the 26S proteasome. Tat also binds to HIV-1 Tat interactive protein, 60kDa (HTATIP) and HIV-1 Tat interactive protein 2, 30kDa (HTATIP2). TAR is also bound by TAR (HIV) RNA binding protein 1 (TARBP1), TAR (HIV) RNA binding protein 2 (TARBP2) and TAR DNA binding protein (TARDBP). Tat 48-60 and Tat 47-57 are used as cell-penetrating peptides (CPPs). It has a basic domain for binding to cell membranes after secretion. Interaction between HIV-1 Tat and pRb2/p130 is a possible mechanism in the pathogenesis of AIDS-related neoplasms^ref. Possible molecular mechanisms for the pro-apoptotic effect of Tat involve the cell's microtubular network and the mitochondrial pathway of apoptosis^ref.
• Rev / p19 is produced by the 2 kb transcript. It binds to importin b to enter nucleus, where it is detached by RanGTP and binds to Rev-responsive elements (RRE) within env and protects the pre-mRNA from being spliced by protecting donor and acceptor splicing sites. The NES of Rev binds crm1 allowing export into cytosol, where RanBP1 and RanGAP detach the viral pre-mRNA from Rev and crm1 allowing the transcription of longer polypeptides
• a single spliced 4.3 kb transcript which codes for Tat, Rev and Nef.
• an unspliced 9.2 kb transcript which codes for gag and pol and represents the genomic RNA
Such splicing impairment is
It also binds to HIV-1 Rev binding protein (HRB) and HIV-1 rev binding protein 2 (HRB2). Rev 34-50 is used as a cell-penetrating peptide (CPPs).
• virion infectivity factor (Vif) / p23 protein inhibits the cellular cytidine deaminase APOBEC3G / CEM15 cytidine deaminase and APOBEC3F in nonpermissive cell lines by inhibiting mRNA translation and enhancing proteasomal degradation independently of other viral proteins^{ref1, ref2, ref3}, allowing HIV-1 multiplication even in these cells. HIV-1 deleted for the vif accessory gene encapsidates the APOBEC3G. Upon infection, the encapsidated APOBEC3F and APOBEC3G induce G=>A mutations in the viral reverse transcripts
• Vpr / p15 protein is found in virions, is peculiar to most evoluted retroviruses, and blocks cell cycle in G₂ phase upregulating viral genome transcription. It also has glucocorticoid receptor coactivator activity, potently increasing the sensitivity of glucocorticoid target tissues to cortisol, leading patients with AIDS and normal cortisol secretion to manifestations compatible with glucocorticoid hypersensitivity of the immune system, such as suppression of innate and cellular immunities.
• viral protein U (Vpu) / p16 is an integral membrane protein which detaches CD4 from Env during unproper binding in the ER or Golgi, allowing Env to reach the plasma membrane. It can disrupt NFkB-mediated innate responses.

The emergence of HIV-1 escape mutations (due to both lack of proof-reading activity of HIV-1 reverse transcriptase and activity of human APOBEC3G / CEM15 cytidine deaminase) depends on the balance of selective pressure - exerted by numerous factors, such as CTL frequency (up to 19% of host CD8⁺ CTL are specific for Tat and up to 37% of CD8⁺ CTLs are specific for Rev : anyway CD8⁺ CTLs are no longer effective in late stages due to antigenic shift of wild-type virions), epitope specificiy, properties of the TcR and the functional state of CTL - and the cost of the mutation to virus fitness. Reduced B-cell expression of CD25 / IL-2R results in reduced ability to proliferate. Anyway, even when present, the viral inhibitory activity of neutralizing antibodies results in complete replacement of neutralization-sensitive virus by successive populations of resistant virus with mutations in the env gene : these mutations are unexpectedly sparse, don't map generally to known neutralization epitopes, and primarily involve changes in N-linked glycosylation. The neutralizing HIV-specific antibody 2G12 - isolated from an infected patient - rather than binding gp120 as a monomer, forms a dimer in which their VH domains are swapped : the result is an extended multivalent antigen-binding site that can recognize the close repeating pattern of oligomannose residues that mask the surface of gp120 (a conventional antibody could never achieve this due to steric constraints). Whereas the sugars on the surface of gp120 are closely clustered, on host proteins the same sugars tend to be widely spaced, so the unusual antibody structure allows the recognition of a unique feature of the virus.
In absence of escape mutants low-level rebound may have originated from activated reservoirs of previously infected cells, with the activation caused by infection with syphilis.
HIV-1 has been reported to acquire a considerable number of cell surface proteins (including CD3deg, CD11a / LFA-1, CD11b / Mac-1, CD18, CD25, CD28, CD43, CD44, CD54 / ICAM-1, CD55 / DAF, CD59 / protectin, CD63, CD71 / TfR, and class II MHC molecules) upon budding at the site of cell-to-cell contact. The physical presence of host-encoded CD55 and CD59 was found to protect from complement-mediated virolysis. The incorporation of ICAM-1 renders HIV-1 virions less susceptible to Ab-mediated neutralization.
Susceptibility / rapid progression to AIDS:
• homozygosis for class I MHC loci
• HLA-A1
• HLA-Aw19
• HLA-A24
• HLA-B7 supertype : variation in viral set-point, in absolute CD4 count and, by inference, in rate of disease progression, is strongly associated with particular HLA-B but not HLA-A allele expression. Moreover, substantially greater selection pressure is imposed on HIV-1 by HLA-B alleles than by HLA-A. Furthermore, HLA-B gene frequencies in the population are those likely to be most influenced by HIV disease, consistent with the observation that B alleles evolve more rapidly than A alleles^ref.
• HLA-B8
• HLA-B35
• HLA-Cw*04
• HLA-C7
• HLA-DR3
• HLA-DR4
• HLA-DQ1
• HLA-DQB1*0302
• HLA-A1-B8-DR3
• TAP1
• TAP2
• CX₃CR1 I249 or M280
• IL-10-5'592A
• abuse of exogenous opioids agonists play a significant role in the susceptibility of the CNS to HIV-1 infection and subsequent encephalopathy by inhibiting local production of HIV-1-protective chemokines (CXCL8 / IL-8 and CCL-4 / MIP-1b) and enhancing expression of HIV-1 entry coreceptor genes (CCR3, CD195 / CCR5, and CXCR2) within the CNS. These effects of opioids appear to be mediated through the opioid m receptor that is expressed on astroglial cells.
• opsonization of HIV-1 by semen C3a enhances infection of CR3-expressing cells
• superinfection from a different strain may occur even in individuals who have immunity to their initial infection
• human immunodeficiency virus type 1 (HIV-1) expression (elevated) 1 (HIVE1)
Resistance :
• resistance to infection :
• homozygous CCR5-D32 (resulting in a truncated protein that remains within the cell; this alteration doesn't affect the health of homozyogous carriers, indicating that its functions are dispensable; this allele has been positively selected in Caucasians 700 years ago : although the allele confers resistance against HIV-1, HIV has not existed in the human population long enough to account for this selective pressure. The prevailing hypothesis is that the selective rise of CCR5-D32 to its current frequency can be attributed to bubonic plague but CCR5 knockout mice (a species which is susceptible to pulmonary but not to bubonic plague) are not protected against Yersinia pestis infection after all^ref : smallpox is more consistent with this historical role^ref, but it has only been a serious threat in Europe since the 1600s, which may not have been enough time to have such a big genetic effect. But the influence of smallpox over the centuries may have been underestimated, because it largely affected children. The average frequency of this allele is 10% in European populations. A mathematical model based on the changing demography of Europe from 1000 to 1800 AD demonstrates how plague epidemics, 1347 to 1670, could have provided the selection pressure that raised the frequency of the mutation to the level seen today. The original single mutation appeared over 2,500 years ago and that persistent epidemics of a haemorrhagic fever that struck at the early classical civilisations served to force up the frequency to about 5x10^-5 at the time of the Black Death in 1347. Around 1900, historians spread the idea that the plagues of Europe were not a directly infectious disease but were outbreaks of bubonic plague, overturning an accepted belief that had stood for 550 years. Professor Duncan and Dr Scott illustrated in their book, Return of the Black Death (2004, Wiley), that this idea was incorrect and the plagues of Europe (1347-1660) were in fact a continuing series of epidemics of a lethal, viral, haemorrhagic fever that used the CCR5 as an entry port into the immune system. Using computer modeling, they demonstrated how this disease provided the selection pressure that forced up the frequency of the mutation from 1 in 20,000 at the time of the first Black Death epidemic (which killed some 40% of Europeans between 1347 and 1350) to values today of 1 in 10. Lethal, viral haemorrhagic fevers were recorded in the Nile valley from 1500 BC and were followed by the plagues of Mesopotamia (700-450BC), the plague of Athens (430BC), the plague of Justinian (AD541-700) and the plagues of the early Islamic empire (AD627-744). These continuing epidemics slowly raised the frequency from the original single mutation to about 1 in 20,000 in the 14th century simply by conferring protection from an otherwise certain death^ref. Haemorrhagic plague did not disappear after the Great Plague of London in 1665-66 but continued in Sweden, Copenhagen, Russia, Poland and Hungary until 1800 : this maintenance of haemorrhagic plague provided continuing selection pressure on the CCR5-D32 mutation and explains why it occurs today at its highest frequency in Scandinavia and Russia : people in Finland and Russia have the highest level, around 16%, whereas a mere 4% of Sardinians possess it
• individuals carrying extra copies of CCL3L1 gene (one of several cytokine genes clustered on 17q whose product binds to several chemokine receptors including CCR9 / chemokine binding protein 2 and CCR5 / CD195, a co-receptor for HIV, and binding of this protein to CCR5 inhibits HIV entry. The copy number of this gene varies among individuals; most individuals have 1-6 copies in the diploid genome, although rare individuals have 0 or > 6 copies. The human genome reference assembly contains two full copies of the gene and a partial pseudogene. This record represents the more telomeric full-length gene.) are less likely to contract HIV or to progress to full-blown AIDS. African populations have an average of 6 copies, whereas non-African populations have half that number. Regardless of the absolute number of gene copies in a population, those with a below-average number within their population are more likely than their fellows to contract HIV, and more likely to develop AIDS if they are infected. This heightened disease susceptibility is exacerbated in those who also have a 'high-risk' variation of the CCR5 gene. The team estimates that around 40% of the risk of HIV infection can be explained by these two genes.
• HLA-A28
• HLA-Bw70
• HLA-Aw69
• HLA-B18
• rhesus macaques with SNPs in TRIM5a, which intereferes with coat shedding. TRIM-Cyp fusion protein arose after the divergence of New and Old World primates when a LINE-1 retrotransposon catalysed the insertion of a cyclophilin A (CypA) complementary DNA into the TRIM5 locus : this retrotransposition explains owl monkey post-entry restriction to HIV-1^ref. The mouse retroviral-restriction factor Friend-virus-susceptibility factor 1 (Fv1), derived from an endogenous retroviral Gag protein, protects against infection with murine leukaemia virus (MLV), with the 2 main alleles, Fv1ⁿ and Fv1^b, conferring resistance to different strains of MLV (B-MLV and N-MLV, respectively). Although the mechanism of action of Fv1 is unknown, it seems to involve an effect on viral capsid (CA) proteins, because polymorphism at position 110 of MLV CA determines the B- or N-tropism. Since the description of Fv1 more than 30 years ago, it has been shown that cells from other mammals can also restrict N-MLV, but not B-MLV, infection in a CA110-dependent manner; the corresponding human activity is known as restriction factor 1 (Ref1) and the simian activity is known as lentiviral-susceptibility factor 1 (Lv1). Ref1 and Lv1 are actually species-specific variants of TRIM5a^{ref1, ref2} : Fv1 lies upstream of and depends on TRIM5a for its activity. In addition to MLV, TRIM5a can also restrict infection with other retroviruses, depending on the species. For example, TRIM5a from African green monkeys, but less so from humans, could restrict HIV-1^ref. Also, TRIM5a from African green monkeys could restrict infection with a strain of simian immunodeficiency virus (SIV) from macaques but not an SIV strain from African green monkeys. Therefore, TRIM5a might have evolved to prevent cross-species retroviral transmission and that for a particular retrovirus to colonize a new species requires adaptation to avoid species-specific TRIM5a-mediated restriction — probably by mutations in the CA protein^ref. Given that the TRIM motif is shared by proteins encoded by > 30 genes in the human genome, this interest in TRIM5a might lead to the discovery of a family of TRIM factors that restrict different viruses : indeed, TRIM1 from African green monkeys, humans and owl monkey kidney cells could restrict N-MLV^ref.
• rapid elimination of HIV-1 infection :
• HLA-A26
• HLA-B38
• TAB1
• TAB4
• TAP2
• TAP3
• long term survivors : alive > 10 years after infection
• slow progressor (SP) : CD4⁺ lymphocyte count has declined to 500 cells / mL.
• long-term non progressors (LTNP) (< 5%) : always remained asymptomatic with a CD4⁺ lymphocyte count > 500 / mL without antiretroviral drugs.
• defects in HIV-1 nef gene and/or U3
• heterozygous CCR5-D32 or other CCR5 promoter SNPs
• heterozygous CCR2-V64I (due to ability to heterodimerize with CXCR4 / CD184 / fusin / LESTR, downregulating its surface expression)
• homozygous 3'UTR-A801 SDF-1 (its upregulation allows more effective competitive inhibition of HIV-1 binding to CXCR4 / CD184 / fusin / LESTR)
• CCL-5 / RANTES-28G (its upregulation allows more effective competitive inhibition of HIV-1 binding to CD195 / CCR5)
• maximal heterozygosis in class I HLA genes
• HLA-A11 haplotype
• HLA-A32 haplotype
• HLA-Bw4-80Ile
• HLA-B13 haplotype
• HLA-B27 haplotype / supertype
• HLA-B51 haplotype
• HLA-B57 haplotype
• HLA-B*5701
• HLA-B58 supertype
• HLA-C2 haplotype
• HLA-DQA1*0301
• HLA-DQB1*0302
• HLA-DQB1*0303
• HLA-DRB1*0400
• HLA-DRB4*0101
• in 1986, Levy's lab described an activity in nonprogressors' CD8⁺ T lymphocytes that halted the replication of the virus without killing the infected cells : the CD8⁺ cell antiviral factor (CAF)^ref has been identified partly with b-chemokines CCL3 / MIP-1a, CCL-4 / MIP-1b and CCL-5 / RANTES (competitive inhibitors of binding to CCR5 / CD195, so expecially effective against M-tropic / R5 strains). HIV-specific CD8⁺ T lymphocytes from LTNPs have incresed proliferation rate and perforin expression compared to those from progressors.
• neutrophils produce a-defensins-1, -2 and -3 (effective against both strains)
• co-infection with HTLV-2 can potentially interfere with the replicative capacity of HIV-1 by up-regulating the secretion of HIV-1 suppressive chemokines, in particular CCL3 / MIP-1a.
• co-infection with Hepatitis GB virus C (HGBV-C)
Transmission :
• horizontal transmission :
• blood and derivatives : viremia is higher during the acute and very late stages
• sexual route : strains transmitted by this route express a shorter gp120 isoform which increases attachment to cell surface but increases susceptibility to antibodies by 10-folds. Peripheral blood CD4⁺ T cells isolated from women who have unprotected sexual intercourse with the same man for > 1 year (and to a much lesser extent men with the same female partner) are highly resistant to both CCR5 and CXCR4 binding strains of HIV-1 in vitro: mucosal alloimmunisation might be a novel vaccination strategy to induce protection against HIV-1. A link between reactivity to foreign histocompatibility antigens and resistance to infection with simian immunodeficiency virus (SIV) was first observed in the early 1990s. Macaques immunised with inactivated SIV cultivated in a human T-cell line or with the uninfected cells had equal protection on challenge with virus grown in the same cell line, indicating that protection was mediated by xenoimmunisation against host-cell proteins in the vaccine. SIV and HIV-1 can incorporate considerable quantities of selected host-cell antigens, including MHC class I and II molecules, as they bud from infected cells^{ref1, ref2, ref3} and the frequency of antibodies against these components correlate with protection against SIV^ref. Xenoimmunisation of macaques and alloimmunisation of women also induces significant quantities of CD8⁺ T-cell-derived antiviral factors, including CC-chemokines^{ref1, ref2} and an increase in resistance of CD4⁺ T cells to in-vitro HIV-1 infection^ref. That reduced mother-to-infant transmission of HIV-1 correlates with an increased MHC class I disparity and that HIV transmission is more frequent in uniparous compared with multiparous women supports the idea that natural alloimmunisation may also decrease susceptibility to HIV-1^{ref1, ref2}. Alloimmunisation has been proposed as one such strategy because it could provide sterilising immunity through induction of antibodies and cellular immunity that together might eliminate free virus, productively infected cells, and pro-virally infected cells during a transmission event^ref. If infection did occur, alloimmunisation would also provide a second line of defence via induction of CD8⁺ T-cell-derived antiviral factors^ref.  However, the overall effect of allostimulation on HIV-1 infection is complex, and alloresponses, in general, may not always lead to protection or control. Both in-vitro and in-vivo exposure to allogeneic leucocytes is reported to stimulate HIV-1 replication in already infected cells^{ref1, ref2, ref3}. HIV-1 immunogen (inactivated envelope-depleted HIV-1 coupled with incomplete Freund's adjuvant), an immunological modifier which contains substantial amounts of host-cell proteins, did not increase HIV-1 progression-free survival when used as a therapeutic vaccine in a large clinical trial^ref. Furthermore, a study in serodiscordant couples, albeit in small numbers, failed to show that histocompatibility discordance was a major factor in non-transmitting couples^ref. It could also be argued that individuals who have unprotected intercourse with multiple partners should generate an extensive primed allorepertoire. Although a small cohort of highly exposed persistently seronegative female sex-workers have been identified, most epidemiological evidence indicates that unprotected intercourse dangerously exposes most individuals to HIV-1 infection. Peters and colleagues did not show data about the allospecific immune response in the genital tract, the main site of transmission of HIV-1, where sterilising immunity must occur and yet where the immune repertoire in the female needs to be tolerant to paternal (partner) transplantation antigens. Certainly their findings suggest that regular sex, like pregnancy, results in a boosting of the MLR to partner antigens in the peripheral blood. Because the seminal antigens of a male partner are, however, by definition, shared with those of the fetus of an ensuing pregnancy, the strength and quality of the local immune response would be expected to be of paramount importance. Successful pregnancy may, in fact, be associated with repeated exposure to semen from a specific mate^{ref1, ref2, ref3} and is characterised by an influx of immune cells and subsequent hypertrophy of lymph nodes draining the genital tract which is suggestive of induction of an immune response^{ref1, ref2, ref3, ref4}. Experiments in mice suggest this finding is due to the generation of active immunological tolerance, and that seminal-fluid priming prevents rejection of tumours with the same male background, even in the absence of an ensuing pregnancy^ref. Such an effect is probably due to the presence of extraordinary concentrations of TGF-ß found in semen (and also 19-hydroxy-PGE in human semen), which can skew local immune responses to a T_h2 phenotype, induce suppressive T_h3 and T_r1 lymphocytes subsets, and down-regulate the activity of any T_h1-effector cells^{ref1, ref2, ref3}. Hence the post-coital immune recognition of male alloantigen in the female genital tract might routinely result in active local tolerance. Reproduction-driven cervical immune privilege prevents rejection of other antigenically foreign cells, such as preneoplastic and neoplastic cells infected with HPV. It is more difficult to conceive whether down-regulation of the local male response to female transplantation antigens would be evolutionarily warranted. However, the natural tendency in the male genital tract, as a component of the mucosal immune system, could be towards tolerance in the absence of danger signals. Immune responses, when they occur in the mucosae, might also be compartmentalised and not reflect events in the peripheral blood^ref. These observations must never, of course, be interpreted as a suggestion for individuals to have unprotected intercourse for the purpose of alloimmunisation^ref. Newly infected cells were detected in the cervical submucosa 3-4 days after exposure to a primary HIV isolate. At earlier times, extensive and stable binding occurred when cervical surfaces were exposed to virions or seminal cells. Cervical mucus provided some protection for the endocervical surface, by physically trapping virions and seminal cells. Confocal microscopy combined with 3D surface reconstruction revealed that virions could both bind to the external surface of the cervical epithelium and actually penetrate beneath the epithelial surface. In quantitative assays, pretreatment with a blocking antibody directed against b₁ integrin reduced HIV virion binding. Collectively, these results highlight a continuum of complex interactions that occurs when natural sources of HIV infectivity are deposited onto mucosal surfaces in the female reproductive tract^ref.
• woman-to-woman^ref
  
• blood transfusion (tested by Procleix^®) (rare nowadays)
• scintigraphy with radiotracer-labelled leucocytes
• piercing, tattooing
• other biological fluids (> 400 mL saliva, ...)
• zooanthroponosis (resérvoir : Pan troglodytes troglodytes)
• laboratory infection
• HIV-1 can not replicate in arthropod salivary gland cells (mosquito (Toxorhynchites amboinensis^ref), bed bug (Cimex hemipterus^ref), flea, Ornithodoros moubata^ref) due to lack of T4 antigen on cell surface; low viral titres in body fluids and the short survival of the virus in the mosquito (1-2 days, the time required for the mosquito to digest the blood-meal) render the risk of mechanical transmission extremely low or nonexistent : It has been calculated that, for mechanical transmission, an AIDS-free individual would have to be bitten by 10 million mosquitoes that had been feeding on an HIV carrier to receive a single unit of HIV from contaminated mosquito mouthparts
• vertical transmission :
• the HIV virus cannot penetrate the sperm cells, but is contained in seminal fluid and at times white blood cells. Sperm washing uses centrifugal force to separate out the different cellular components of the semen. The healthiest of the motile sperm will swim up to the top of the solution where they are harvested and tested for HIV. The final sample of sperm is free of the fluid and non-sperm cells which can carry the virus. This is then inseminated into the female partner at her most fertile time of the month. This is done either through in vitro fertilization in a laboratory culture dish, or directly injected into a woman's uterus (intrauterine inseminations).
• CDC estimates that some 300 or so U.S. infants are born each year infected with HIV, despite recommendations for prenatal HIV testing and for use of AIDS drugs during pregnancy in infected women. An estimated 700,000 children worldwide developed HIV infections last year, most in Africa and from mother-to-child transmission during childbirth or early infancy. The problem is especially acute in southern Africa, where about 1 in 5 pregnant women has HIV but is unaware of it and many don't see a doctor until giving birth.Without drug treatment before birth for mothers and shortly thereafter for newborns, babies born to infected women have a 25-30% chance of becoming infected. With optimal treatment of the mother, the transmission rate drops to < 2%. The odds increase if the mother isn't treated until she's in labor, but that's still better than no treatment at all.
• placental route (the placenta protects most unborn children from HIV. Infection only becomes likely if the placenta is damaged, or after it breaks naturally, during labor => prevention by Caesarian section)
• lactation : babies of HIV-positive mothers stand a 15% chance of becoming infected during breast-feeding. Milk formula isn't available to many in poorer countries. And a lack of breast milk has long-term health effects, including increased susceptibility to respiratory diseases - a major killer of infants in the developing world. Additionally, if there's not enough food or if you can't afford the formula or if people are diluting down the formula, what you get is a baby that dies of malnutrition. Anyway a baby's chance of contracting HIV falls to <1% if they receive antiretroviral drugs while being nursed and the doses needed to protect babies are a fraction of those used to treat adults, and they are only necessary for the first 6-12 months of a child's life. So some might argue that treating infants is an affordable alternative to treating their mothers, but nursing mothers must also receive medication so that they can live to look after their children. But researchers estimate that only 1% of adults in sub-Saharan Africa have access to antiretroviral drugs. Breastfeeding causes nearly 40% of all pediatric HIV infections, yet also prevents millions of child deaths every year by protecting infants from diarrhea and other infections. Exclusive breastfeeding substantially reduces the transmission of HIV from mother to infant and infant death, compared with partial breastfeeding. Infants who were introduced to solid foods or animal milk within the first three months were at four times greater risk of contracting HIV through breastfeeding compared to those who were exclusively breastfed^ref. International guidelines currently recommend that HIV-infected mothers should avoid all breastfeeding, but only if replacement feeding is acceptable, feasible, affordable, sustainable and safe : for the large majority of African women, this isn’t the case and breastfeeding is the only choice. These findings indicate that for these mothers, delaying introduction of all non-breast milk foods will substantially reduce the risk of HIV and death for their infants
Prevention : an HIV⁺ mother is given a single dose of nevirapine during labor and her baby gets one dose within 48 hours of birth. The baby has active levels in its bloodstream for at least the first week of life, hence being protected even during the early period of breastfeeding. Researchers are looking at the benefits of giving babies a drug such as nevirapine once a day for the first 6 months while they're breastfeeding, then having an early weaning. The ability to screen women rapidly for HIV infections and offer antiretroviral therapy has the potential to prevent HIV transmission to hundreds of thousands of infants that otherwise might occur. Orasure Technologies' OraQuick test involves a finger-prick blood test and was approved for U.S. use in 2002 : it takes an average of 66 minutes to test, get results and explain them to the women - plenty of time to begin treatment while labor is still progressing. High sensitivity but poor specificity require confiration with conventional tests. Treatment for HIV-exposed infants is generally AZT (zidovudine) syrup every 6 hours for 6 weeks; some also get a single dose of nevirapine, an inexpensive AIDS drug shown to help prevent mother-to-child transmission. Infected mothers also get AZT and some received nevirapine, too.
Pathogenesis :
• anti-lymphocyte antibodies (ALA), mainly IgM, have been detected in the plasma of 53.8^ref-75% (of 78)^ref of HIV-positive patients tested. ALA bind to both CD4⁺, CD8⁺, and B lymphocytes, but not to monocytes. ALA could not be detected in the plasma of normal subjects, patients with acute renal failure undergoing renal dialysis, or patients with high levels of circulating immune complexes^ref : antigenic specificities of ALA in HIV infection are resistant to pronase treatment and are not related to CD4 and CD8 molecules^ref
• anti-lymphocytic ganglioside antibodies were detected in 23 out of 49 AIDS patients sera (46.9%). All positive sera reacted selectively with the GM₃ comigrating band from AIDS lymphocytes. 22 out of the 23 anti-lymphocytic GM₃ positive sera also had antibodies against CD4⁺ T cells, versus 17/26 anti-GM₃ negative. Furthermore, patients with lymphocytic GM₃ antibodies showed a significantly higher antibody reactivity against CD4⁺ T cells than patients in which these antibodies were not detected.The absorption tests revealed that preincubation of positive sera with GM₃ was followed by a decrease in the reaction with target lymphocytes. These findings suggest that anti-GM₃ antibodies are a portion, but not the majority, of antibodies reacting with CD4⁺ T cells^ref.
• MHC class II^- T cells showed a stronger reaction with anti-lymphocyte antibodies than B cells or MHC class II⁺ T cells. Patients with antibodies against CD4 lymphocytes showed a significantly higher antibody reaction with the retroviral antigen gp41 than patients without these antibodies. An association between anti-lymphocyte antibodies and antibody reactivity against other HIV-1 antigens was not noticed^ref.
• antibodies elicited by HIV infection can interact with antibodies elicited by cofactor infections (HIV-CMV; HIV-HBV; HIV-tuberculosis; HIV-mycoplasmas; HIV-S. aureus; and CMV-mycoplasmas) to form CIC, and some of these antibodies mimic ALA so that they may function as LCTA^ref
• directed against OKT4⁺ or OKT11⁺ cells whereas OKT8⁺ cells showed no detectable reactivity (a population of T cells that is predominantly composed of helper cells and does not include suppressor cells)^ref
ALA proved to be useful prognostic indicators for the course of the HIV infection^ref. There was a statistically significant correlation of increased Ig+ cells with HIV infection, decreased CD4/CD8 ratios, increased serum neopterin levels, and abnormal in-vitro responses to pooled allogeneic stimulator cells or CD3 monoclonal antibody. Patients with ALA were lymphopenic, had decreased absolute counts of CD4⁺, CD25⁺, CD21⁺ and OKM5⁺ cells, and higher percentages of CD8⁺ and OKIa1⁺ cells in their blood than patients without ALA^ref. ADCC against non-T cells and lymphoblastoid cell lines (P3HR-1K and Raji) were detected in AIDS patients and in homosexuals and haemophiliacs with positive or negative HIV serology. Anti-class II antigen specificity was revealed by experiments in which class II antigens on target cells were blocked with monoclonal anti-class II antibody (DA6,231) and the cytotoxic reaction induced by patient's sera was abolished. In contrast, ADCC was not impaired by preincubating the target cells with anti-class I monoclonal antibody (W6/32)^ref. Of homosexuals individuals whose sera contained ALA, 71% of ARC patients and 83% of healthy (anti-HIV Ab negative) homosexuals had antibodies recognizing a 73 kDa molecule. ALA present in ARC sera reacted with CD3⁺, CD4⁺ and CD8⁺ lymphocytes while little reactivity with B cells was observed. Our results indicate that ALA appear in homosexuals prior to HIV infection and are reactive primarily with T lymphocytes. A 73 kD structure associated with the T cell membrane is frequently the target for these antibodies^ref. The sperm has been proposed to be the cause of AIDS, selectively accepting into its interior only macrophage-tropic HIV through its CD4⁺ antigens and carrying this HIV into a person through 4 possible pathways: rectum (anal sex), genital ulcers, blood transfusions, and female circumcision. Then the sperm acts as a 'Trojan horse' by entering HLA-DR⁺ CD4⁺ T cells and releasing the HIV into these cells. The released HIV in turn mutates to a form capable of attacking CD4⁺ T cells. Thus the sperm by a 'Trojan horse' mechanism has changed the tropism of HIV. However, experimental evidence indicates that this mutated HIV is essentially non-toxic. In contrast, it is concluded that the sperm is extremely toxic since it is capable of inducing autoimmune reactions (by means of its CD4⁺ antigens) and is capable of entering and destroying HLA-DR⁺ CD8⁺ and HLA-DR⁺ CD4⁺ T cells in either the presence or absence of HIV (AIDS or ICL). Hence, the mysteries of AIDS can be explained by the presence of the toxic sperm and its complicated interactions with HIV (the 'Trojan horse' mechanism)^ref.
• antibody-dependent enhancement (ADE) of viral infection
• astrocytes can be infected by primary HIV-1 isolates via a mechanism independent of CD4 or major chemokine receptors
• Hin-1 protein is found only in HIV-1 infected cells
• HIV-specific CD8⁺ T cells produce antiviral cytokines but are impaired in cytolytic function : they express significantly lower levels of perforin and have persistent CD27 expression (suggesting impaired maturation)^ref
• individuals with advanced HIV-1 infection have higher proportions of T cells that are short lived, in both the CD4⁺ and CD8⁺ memory/effector T-cell subpopulations, compared by healthy controls. In advanced HIV-1 infection, total pool sizes of short-lived cells are only moderately affected, whereas the size of the long-lived pool is reduced by a factor > 4. This indicates that patients with HIV-1 have a reduced ability to generate long-lived progenitor cells for maintaining the T-cell pool. Effective treatment with HAART is able to restore the capacity to generate these progenitor cells, by reducing the levels of T-cell proliferation and T-cell death in infected individuals. These data provide evidence against a model in which the characteristic depletion of CD4⁺ T cells that occurs in HIV-1 infection results from direct HIV-mediated cell killing, as long-lived progenitors of both CD4⁺ and CD8⁺ T-cell subpopulations are reduced in patients infected with HIV-1. Moreover, they favour a model in which increased levels of proliferation of effector/memory T cells in HIV infection reflect chronic activation^ref
• A146P SNP in Gag is more common in patients expressing the MHC class I molecule HLA-B57 as the result of selection pressure (may arise in an HIV⁺ HLA-B57⁺ child of an infected HLA-B57^- mother), and is associted with a 22-fold increase in viral load compared with wild-type virus, resulting in an increased risk of progression to AIDS. The A146P mutation affects the pathway by which proteins become processed (ERAP1 /ARTS1 can not cut amino-terminal extended ISW9 peptides that contain proline rather than alanine at residue 146) and presented on MHC molecules, and therefore indirectly prevents lysis by CTLS specific for the epitope ISW9 (residues 147-155), which doesn't contain residue 149^ref.
• given that the gastrointestinal tract and other lymphoid tissues harbour most of the body’s CD4⁺ T cells and that, in the gut, a large number of these cells are activated and express the HIV co-receptor CCR5, the intestinal CD4⁺ T cells are potentially highly susceptible to infection with HIV. In fact the gastrointestinal tract has the most marked depletion of CD4⁺ T cells. Specifically, deletion mainly occurred in the effector sites (the lamina propria) as opposed to the inductive sites (Peyer’s patches and lymphoid follicles) of the gut mucosa. This deletion occurs rapidly and at all stages of HIV infection (before changes observed in the blood), regardless of administration of HAART for up to 5 years, which on the other side restores normal CD4⁺ T-cell numbers in the blood. Disrupted lymphoid architecture (increased T-cell activation is associated with collagen deposition in the lymph nodes) might disturb normal lymphoid-tissue homeostasis, which might then impair CD4⁺ T-cell reconstitution of the gut following depletion by infection with HIV^{ref1, ref2}. In monkeys, within a few days of infection, SIV infects up to 60% of memory CD4⁺ lymphocytes, and it goes on to kill about 50% of them. These cells are responsible for remembering infectious agents and triggering the immune system to attack them. The virus worms its way into all of the cells it kills, but also triggers cell suicide in many cells without actually invading them. The idea that HIV inflicts severe damage very early in infection stemmed from a 1998 paper showing that SIV quickly obliterates CD4⁺ cells in the guts of monkeys : the slow crumbling of patients' immune systems, and their increased vulnerability to infection, is triggered by the early viral damage. You have a massive wound in the first 3 months of infection and the patient dies slowly as a result : if this is true, then the number of immune cells killed by HIV in its first few days might be used to predict how quickly the disease will advance in a particular patient. The realization could also prompt changes in the way experimental vaccines are devised and tested. It suggests that a jab must stop the infection at its earliest stages: perhaps by working in the gut, where the destruction of immune cells is most dramatic.  The results also back the case for giving drugs as a preventative measure to groups at very high risk of infection, such as sex workers, to prevent the virus gaining a foothold. And researchers may need to find ways of supplementing existing antiviral drugs with treatments that regenerate the devastated population of memory CD4⁺ cells
• aberrant polyclonal B cell activation and hypergammaglobulinemia with many autoantibodies : B cells from patients show impaired reactivity to immunisation and in vitro activation signals^ref. During frank loss of immunocompetence, autoimmune diseases that are predominantly T cell subtype CD8 driven predominate. In stage I there is the acute HIV infection, and the immune system is intact. In this stage, autoimmune diseases may develop. Stage II describes the quiescent period without overt manifestations of AIDS. However, there is a declining CD4 count indicative of some immunosuppression. Autoimmune diseases are not found. During stage III there is immunosuppression with a low CD4 count and the development of AIDS. CD8 T cells predominant and diseases such as psoriasis and diffuse immune lymphocytic syndrome (similar to Sjogren's syndrome) may present or even be the initial manifestation of AIDS. Also during this stage no autoimmune diseases are found. In stage IV there is restoration of immune competence following HAART. In this setting, there is a resurgence of autoimmune diseases. The frequency of reported rheumatological syndromes in HIV-infected patients ranges from 1 to 60%. The list of reported autoimmune diseases in HIV/AIDS include systemic lupus erythematosus (SLE), anti-phospholipid syndrome, vasculitis, primary biliary cirrhosis (PBC), polymyositis, Graves' disease, and idiopathic thrombocytopenic purpura (ITP). Also, there is an array of autoantibodies reported in HIV/AIDS patients which include anti-cardiolipin, anti-b₂ GPI, anti-DNA, anti-small nuclear ribonucleoproteins (snRNP), anti-thyroglobulin, anti-thyroid peroxidase, anti-myosin, and anti-erythropoietin antibodies. The association of autoantibodies in HIV-infected patients to clinical autoimmune disease is yet to be established. With the upsurge of HAART, the incidence of autoimmune diseases in HIV-infected patients is increasing^ref.
• HIV infection leads to a state of chronic immune activation and progressive deterioration in immune function, manifested most recognizably by the progressive depletion of CD4⁺ T cells. A substantial percentage of NK cells from patients with HIV infection are activated and express the natural cytotoxicity receptor (NCR) NKp44. A cellular ligand for NKp44 (NKp44L) is expressed during HIV-1 infection and is correlated with both the progression of CD4⁺ T cell depletion and the increase of viral load. CD4⁺ T cells expressing this ligand are highly sensitive to the NK lysis activity mediated by NKp44⁺ NK cells. The expression of NKp44L is induced by the linear motif NH₂-SWSNKS-COOH of the HIV-1 envelope gp41 protein. This highly conserved motif appears critical to the sharp increase in NK lysis of CD4⁺ T cells from HIV-infected patients. These studies strongly suggest that induction of NKp44L plays a key role in the lysis of CD4⁺ T cells by activated NK cells in HIV infection and consequently provide a framework for considering how HIV-1 may use NK cell immune surveillance to trigger CD4⁺ T cells. Understanding this mechanism may help to develop future therapeutic strategies and vaccines against HIV-1 infection^ref.
• HIV-1 meninges and temporal lobe subpopulations evolve about 30 and 100 times faster, respectively, than the other viral populations in the brain. However, maximum likelihood codon-based substitution models did not detect any site under significant positive selective pressure, and the main cause of HIV-1 genetic variation appeared to be random genetic drift. Therefore, the higher evolutionary rate in the meninges and temporal lobe could be due to an enhanced infection/expansion rate of macrophages as a consequence of the immune system failure. In conclusion, in this case study, viral infection in the brain progressed with a nonspecific genetic evolution, recurrent migration events, and an expansion of macrophage-tropic sequences. The data suggest that after immune failure newly produced viral variants, which would be rapidly cleared under normal conditions, begin to productively infect macrophages in a "self-amplifying" cycle of infection/inflammatory response that could be at the origin of HIV-associated dementia^ref
• HIV-1 evolves in vivo under selective pressure from CD8⁺ T-lymphocyte (CTL) responses, which are in turn determined by host and viral genetic factors, such as restricting MHC molecules and the available viral epitope sequences. Identical twins infected with HIV-1 as neonates from a common blood transfusion, with subsequently similar environmental exposures, allows controlled comparisons of CTL targeting and viral evolution. 17 years after infection, their CTL targeting of HIV-1 was remarkably similar. In contrast, their overall TCR profiles were highly dissimilar, and a dominant epitope was recognized by distinctly different TCR in each twin. Furthermore, their viral epitopes had diverged, and there was ongoing viral phylogenetic divergence between the twins between 12 and 17 years after infection. These results indicate that while CTL targeting is predominately genetically determined, stochastic influences render the interaction of HIV-1 and host immunity, and therefore viral escape and CTL efficacy, unpredictable^ref.
• latency occurs in CD4⁺ lymphocytes because RNA polymerase II cannot bind to the proviral long terminal repeat (LTR) because of alterations in the chromatin structure that had been induced by the binding of the histone deacetylase enzyme HDAC1 to the LTR. Inhibition of HDAC1 or knockdown of NF-kB p50 (which recruits and complexes with HDAC1) were sufficient for the production of short nonproductive viral transcripts, and full viral transcription could be achieved by coexpressing the viral transactivating protein Tat. Establishing this mechanism in primary CD4 T cells will be the next step in determining whether combinations of HDAC1 inhibition and Tat activation will prove viable as a means of overcoming latency in the clinic^ref
• The adverse effects of immune activation on CD4⁺ T-cell recovery and the relationship between CD4⁺ T-cell counts and effector T-cell function were examined in HIV-1 patients receiving long-term effective ART. Patients with nadir CD4⁺ T-cell counts <100/ml, > 12 months on ART and >6 months with <50 HIV RNA copies/ml were stratified by current CD4⁺ T-cell counts and patients from the lowest (n = 15) and highest (n = 12) tertiles were studied. Proliferation (Ki67), activation (HLA-DR, CD38) and replicative senescence (CD57) were assessed by flow cytometry and CD4⁺ T-cell responses to CMV by IFN-g ELISpot. Proportions of CD4⁺ T-cells expressing HLA-DR or CD57 were strong univariate predictors of total (P = 0.0002 and P = 0.002) and naive (P < 0.0001 and P < 0.0001, respectively) CD4⁺ T-cell counts, suggesting that CD4⁺ T-cell activation drives the depletion of naive CD4⁺ T-cells. This was clearest in patients with a small/undetectable thymus. IFN-g responses to CMV were similar in patients with low or high CD4⁺ T-cell counts^ref.
• PD-1 is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against PD-L1 restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, PD-1 expression was examined on HIV-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten MHC class I tetramers specific for frequently targeted epitopes. PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection^ref
• changes in paracrine IL-2 requirement, CCR7 expression, frequency, and cytokine secretion, of HIV-specific CD4⁺ T cells are a consequence of antigen load^ref
• preferential depletion of a splenic marginal zone-like peripheral blood CD27⁺B220^- memory B cell population in HIV-1 infected individuals^ref
=> a chronic syndrome
CDC staging, 1987 :
• stage I (only in 50-90% of infected individuals) : acute symptomatic infection was described in 1985^ref (if longer than 14 days, or persistent high [p24], or high [CD38] on CD8⁺ T-lymphocytes, or low [anti-p24 Abs], prognosis is worsened) : intermittent fever, acute pharyngitis, esophagitis, cervical and axillary > inguinal and iliac lymphadenitis (mononucleosis-like syndrome with neither pharyngotonsillitis nor leukocytosis (often leukopenia with relative lymphopenia), thrombocytopenia, dry skin, headache, backeye ache, myoarthralgia, nausea and vomiting, diarrhea, anorexia, cachexia, aseptic meningoencephalitis (Bell's palsy, Guillain-Barré syndrome), myelopathies, morbilliform maculopapular exanthema (expecially in HLA-B62; differently from that caused by Rubella virus, it involves also hand palms and foot soles), mucocutaneous ulcers. Differently from HHV-4 / EBV infection, enanthema is limited to hard palate, acute pharyngitis is not exudative, rash, ulcers and diarrhea occur, while jaundice is rare. CNS invasion by HIV-1 early in the course of infection is common and has been supported by many cerebrospinal fluid studies^ref. Although one early report describes a fatal case of brain involvement during probable primary HIV infection, T-lymphocyte subset data was not reported^ref. HIV stimulates CTL responses in recently infected people. The CTL response initially follows the rise of HIV in the blood, and when that response reaches a peak the virus level falls^ref. In a patient, brain necrosis coincided with the development of CD8-positive lymphocytosis and the disappearance of p24 antigen in the blood. Thus, CTL response rather than HIV virus infection itself may be the cause of brain necrosis; this could not be confirmed postmortem because of extensive necrosis and dexamethasone therapy. Recently, Markowitz et al reported rapid progression in a case of primary MDR HIV infection^ref, but even in the absence of resistance mutations, HIV can rapidly kill^ref.
• stage II : asymptomatic. The bone marrow compensates the 10⁹ CD4⁺ T-lymphocytes that are killed every day : 10¹² new virions are produced => viral charge in blood 10³/mL..
• stage III : lymphadenopathy syndrome (LAS) / persistent generalized lymphadenopathy (PGL) ~ AIDS-related complex (ARC). No sever symptoms are associated : just persistent fever, lymphadenitis, night sweats, slimming, diarrhea, skin inflammatory disease. Expecially in HLA-DR5.
• stage IV : acquired immunodeficiency syndrome (AIDS)
• subgroup A : "constitutional" disease
leukopenia with relative lymphopenia
fever > 38.5 °C and/or diarrhea lasting > 1 month
wasting syndrome / slim disease is a common problem for people with AIDS. Although the exact cause is not well known, several factors contribute to the wasting syndrome. These include poor nutrient absorption, sores in the mouth or throat, which make eating process painful, infections in the gut, diarrhea, drug side effects, altered metabolism and hormone imbalance, and lack of money - the latter being a critical factor in developing countries. These factors work together to accelerate the disease progression and death. Currently, there is no standard treatment for AIDS-associated wasting, which remains poorly treatable even in countries with advanced medical care. Various nutritional supplements, like vitamins, amino acids and lipids can help but their effect is negligible. The appetite stimulants are unfortunately associated with increase in body fat. Hormone treatments including recombinant hGH and synthetic anabolic hormones can also help, but they are extremely expensive and not readily available in poor countries. Not long ago the inclusion of protease inhibitors in HAART was believed to increase the body weight. More recent studies indicated that HAART is associated with redistribution of fat mass from the legs to the trunk with no significant benefit in weight gain. Thus, contrary to the original belief that HAART reverses weight loss the current consensus is that AIDS wasting is not corrected by antiviral drugs. Available treatment options are prohibitively expensive for developing countries where many people often cannot buy even food. Furthermore, AIDS patients with weight loss seldom recover even when given antiviral drugs. V-1 Immunitor treatment results in a sustained and statistically significant increase in body mass in 76% and reduction or clearance of oral thrush in 87.5% of patients^ref.
thrombocytopenia (60%; autoimmune or dysmegakaryopoietic; expecially in HLA-DR5)
anemia (70-90%; 10% in asymptomatic HIV+ patients; caused by opportunistic infections or by past drugs, but no longer macrocytic anemia (MCV > 100 ml in 70%) by HAART (zidovudine))
neutropenia (55% has < 2,000/ml)
• subgroup B : neurological diseases
• AIDS dementia complex / AIDS encephalopathy / HIV-1-associated dementia (HAD)
• vacuolar myelopathy
• peripheral neuropathy
• sicca syndrome (in patients with HLA-DR5 haplotype)
• subgroup C : opportunistic endemic infections (> 1 at the same moment !)
category 1 : AIDS-defining diseases ([CD4⁺]_blood < 50 / mL)
Fungi
Ajellomyces capsulatus => disseminated histoplasmosis
Candida albicans=> esophageal or disseminated candidosis
Cryptococcus neoformans var. neoformans => extrapulmonary cryptococcosis (osteolysis, interstitial pneumonia and meningoencephalitis)
Malassezia furfur=> seborrhoic dermatitis
Pneumocystis carinii => interstitial pneumonia (PCP) => cyanosis.
Bacteria
Mycobacterium tuberculosis (10%, 12 million of patients worldwide, 66% live in Sub-Saharan Africa) => miliary tuberculosis ; chemoprophylaxis when [CD4⁺ T_h lymphocytes]_blood < 200 / mL. Tuberculosis is the leading cause of death in people with AIDS
Mycobacterium avium-intracellulare => meningoencephalitis
Mycobacterium kansasii
Mycobacterium leprae : only about a dozen cases have been described in medical literature since Dr. Lockwood's, a Ugandan exile in London who was being treated for both tuberculosis and AIDS, suddenly developed a swollen lesion on his face in 1983. 7 of these cases are in Brazil, which has the world's highest per-capita leprosy rate and also one of the most effective AIDS treatment programs in the developing world : about 2% of the leprosy cases in Brazil are co-infected with HIV. Not long ago, it had 70% of the world's leprosy cases. Paradoxical exacerbation of disease, when, due to antiviral therapy, an HIV-infected patient's CD4 cell count rises -- is usually referred to as an immune reconstitution inflammatory syndrome (IRIS) or immune reconstitution reaction. IRIS is not necessarily related to ongoing infection per se but can be due to an immune system that has "woken up" and is now reacting, for example, to residual bacterial (such as M. avium-intracellulare), viral (such as cytomegalovirus) or fungal (such as Cryptococcus neoformans) antigens. Whether these reactions described in the posting as occurring after the initiation of antiviral therapy represent an IRIS is not entirely clear. As summarized by Diana Lockwood's group in a review in Lancet Infectious Diseases^ref, some individuals (they review 9 such cases) develop post-HAART reactions as described in the posting, which are similar in most cases to the so called Type 1 "reversal" reactions that are associated with activation of T-cell reactivity to M. leprae antigens, CD4 cell migration into the lesions and production of T_h1-type cytokines, such as IFN-g, IL-2 and IL-12. These type 1 reversal reactions can occur after the institution of therapy for M. leprae. It is important to note, however, that these reactions have now been described in M. leprae/HIV co-infected individuals who have not been treated with antiviral medications. In Sao Paulo, Brazil, 2 such cases are reported that cannot be classified as IRIS in origin^ref. These reactions, in a setting of very low CD4 cell population, underscore the real paradox previously recognized and now discussed by Lockwood's group. The paradox relates to the observation that, despite dramatic effects of HIV/AIDS infection on the clinical manifestations and histopathological findings of M. tuberculosis infection, there is no such effect with M. leprae. Even in individuals with profoundly low CD4 levels who are HIV/M. leprae coinfected, there are granulomas formed in tuberculoid leprosy and the number of CD4 cells in the granuloma were no different than in cases without HIV^ref. The underlying mechanism for this dramatic difference may be related to differences in the mechanism of granuloma formation in the 2 mycobacterial infections, or compartmentalization of the cellular immune response, but still has to be clearly established^ref.
recurrent sepsis by "minor" Salmonella spp.
Protozoa
Cryptosporidium parvum => 13% of all convulsive crisis, diarrhea
Isospora belli => chronic intestinal isosporiasis
Toxoplasma gondii => neurotoxoplasmosis (from cysts reactivation) causes 28% of all convulsive crisis
Leishmania infantum : HIV infection and Leishmania infection each induce important analogous immunological changes whose effects are multiplied if they occur concomitantly, such as a T_h1-to-T_h2 response switch; however, the consequences of the viral infection predominate. In fact, a large proportion of coinfected patients have no detectable anti-Leishmania antibodies. The microorganisms share target cells, and it has been demonstrated in vitro how L. infantum induces the expression of latent HIV-1
Eumetazoa
• Strongyloides stercoralis => extraintestinal strongyloidosis
Viruses
• HHV-2 / HSV-2 => anal infections
HHV-3 / VZV => hematogenous dissemination => multidermatomeric and bilateral zoster
HHV-5 / CMV => chorioretinitis, meningoencephalitis. To determine potential correlates of immune recovery from AIDS-related cytomegalovirus retinitis (CMVR), multiparameter flow cytometry was used to characterize CMV-specific T cells from subjects with CMVR. Individuals with active retinitis were compared with those who had been clinically immunorestored by antiretroviral therapy and had >/=2 years of ophthalmologic follow-up without anti-CMV therapy or retinitis reactivation or progression. In comparison with patients with active retinitis, immunorestored patients had higher circulating CD4⁺ and CD8⁺ T cells expressing IL-2 and IFN-g in response to combined CMV pp65 and IE1 peptide pool stimulation. CD4⁺ T cell responses were predominantly to pp65, whereas CD8⁺ T cell responses were predominantly to IE. Immunorestored patients, compared with patients with active retinitis, had increased levels of circulating CMV-specific CD8⁺ T cells with "early" (CD27⁺CD28⁺CD45RA⁺, CD27⁺CD28⁺CD45RA^-) and "intermediate" (CD27^-CD28⁺CD45RA^-) phenotypes. Recovery from AIDS-related CMVR after the initiation of antiretroviral therapy may be mediated by CMV-specific CD4⁺ and CD8⁺ T cells capable of promoting antigen-specific CD8⁺ T cell proliferation^ref.
JC virus => progressive multifocal leukoencephalopathy (PML) from reactivation (4-7%) : it causes fever, ataxia, behavioural changes, 1% of all convulsive crisis. A much lower incidence of PML has been described in Brazil than in reports from developed countries. A possibility for this discrepancy could be differences in terms of JCV isolates or even the interactions between JCV and local HIV strains. Some particularities about the involvement of the nervous system in Brazilian patients are worthy of note, such as the occurrence of central nervous system involvement in chronic Chagas' disease in patients with AIDS, and the concomitance of leprosy and HIV infection^ref
category 2 : other opportunistic infections
• Bacteria
Nocardia spp.
Mycoplasma pneumoniae
Streptococcus pneumoniae
Treponema pallidum
viruses
HHV-4 / EBV => oral hairy leukoplakia
• molluscum contagiosum virus (5-18%)
• subgroup D : secondary neoplasms due to opportunistic oncongenic viruses in immunosuppresed patients (in 30-40% of patients)
• AIDS-defining cancers :
• Kaposi's sarcoma from HHV-8 / KSV (20-30%, only in male homosexuals; prevalence is decreased by HAART)
• cervical carcinoma from some HPV types
• non-Hodgkin's lymphomas (prevalence is not decreased by HAART) : the risk of developing NHL increased several-hundred-fold among individuals with AIDS^ref, but even at the height of the AIDS epidemic, only a small proportion of all NHL cases occurred in individuals with AIDS^ref. Furthermore, only a few types of NHL have been associated with AIDS, notably primary central nervous system lymphomas (PCNSL) (which causes 4% of all convulsive crisis), high-grade immunoblastic and AIDS-related Burkitt's lymphoma and, to a lesser extent, intermediate-grade large-cell diffuse lymphomas^ref. In contrast, most low- and intermediate-grade lymphomas are not AIDS-associated, including small-cell lymphocytic and follicular lymphomas. Recent advances in the treatment of individuals with AIDS have reduced the risk of both NHL, especially CNS lymphomas, and KS. These findings come from selected populations in longitudinal studies and from data collected soon after the introduction of HAART but before many individuals with AIDS were yet using it^{ref1, ref2}. Therefore, the results of these studies cannot readily be extended to trends of KS and NHL incidence in the general population of the USA. The incidence of these cancers may be affected by trends in the AIDS epidemic, such as the changing degree to which individuals with AIDS take effective antiretroviral therapy and the emergence of HIV resistance to these therapies^ref, by HIV incidence and the proportion of individuals with AIDS who are homosexual men^{ref1, ref2} and, more speculatively, by changes in sexual behaviors that reduce KSHV transmission.
• AIDS-related body-cavity based primary effusion lymphoma (PEL)
• no increased prevalence of T lymphomas although HTLV-1 and HTLV-2 infections are common in HIV-1-infected IDUs
• non-AIDS-defining cancers, are also statistically increased in HIV-infected persons. However, the types of cancer observed at an increased frequency and the relative risks reported vary widely among studies. Although immunosuppression is consistently associated with an increased risk of AIDS-related malignancies, the role of immunosuppression in the pathogenesis of non-AIDS- defining cancers is controversial. Although data regarding the optimal management of these cancers are lacking, current studies suggest that patients with HIV-associated malignancies should be treated with similar approaches to those of their counterparts in the general population^ref.
• nasopharyngeal carcinoma from HHV-4 / EBV reactivation
• AIDS-related lymphomas (ARL)
• non-Hodgkin's lymphomas (NHL) (80-85%)
• Hodgkin's disease (HD) (15-20%) is more aggressive and may eventually have increased prevalence
• basaloid carcinoma / cloacogenic anal carcinoma
• oral cavity squamous cell carcinoma
• hepatocellular carcinoma (HCC)
• non-melanoma skin cancer
• increased prevalence of head and neck, lung, and testicular germ cell cancer is seen nowadays thanks to prolonged life expectancy
• subgroup E : other conditions
• chronic lymphocytic interstitial pneumonia
• clonal expansion of NK cells
• HIV-associated retinopathy
• HIV-associated nephropathy (HIVAN)
CDC staging, 1993 : AIDS
 

[CD4+ Th lymphocytes]blood	A	B	C
> 500 / mL	A1	B1	C1
200 < x < 499 / mL	A2	B2	C2
< 200 mL	A3	B3	C3
 Legend (comparison with 1987 staging) :
• A : stage III
• B : stage IV (subgroups A and C category 2)
• C : stage IV (subgroup C category 1 and subgroup D)
Laboratory examinations :
• very early stages : research of vRNA by ISH in lymph node biopsy
• early stages : research of p24 Ag or vRNA (by Chiron bDNA signal amplification assay or TaqMan 5' nuclease Real-Time PCR).
• late stages :
• ELISA (high sensitivity)
• OraQuick^® (detection of HIV-1 antibodies in 5 mL fingerstick whole blood specimens. The test results are interpreted after 20 minutes but not more than 60 minutes after the introduction of the Test Device into the Developer Solution Vial containing the test specimen with 99% accuracy)
• Calypte Biomedical has recently developed the Calypte AWARE HIV-1/2 OMT antibody test using oral fluid samples^ref
• ... then confirmed by Western blot (high specificity)
A case–control study of 101 blood donors who had been vaccinated against influenza and 191 matched controls showed that recent inoculation with any brand of influenza vaccine was significantly associated with a false positive screening assay for anti-HIV-1, anti-HTLV-1 and anti-HCV antibodies. Surveillance for monthly rates of multiple reactive donations from May 1990 through December 1992 linked the seasonal cluster of multiple false-positive donations to the use of viral screening test kits thought to react nonspecifically to donor immunoglobulin M. There was no similar increasee in multiple false-positive donations during the 1992–1993 influenza vaccination season after the HIV-1 and HCV tests were replaced; however, the number of donations that were falsely reactive for only HTLV-I almost doubled, indicating that false reactivity was not specifically associated with the 1991–1992 influenza vaccine. Retesting of affected donors found that the duration of HTLV-I and hepatitis C virus false reactivity was 3–6 months^ref. Guidelines of both Johns Hopkins and the New York State Department of Health list influenza vaccination as a known cause of indeterminate results on Western blotting for HIV antibodies^ref. Furthermore, digital reconstructions of both molecules demonstrate a striking homology between the transmembrane domains of HIV-1 envelope proteins and the influenza envelope protein hemagglutinin, although whether this homology accounts for the false positive assay reactions is unclear^ref. The HIV GP160 protein exists only in the intracellular domain, where it is cleaved into GP41 and GP120 oligomers. Since GP160 itself is not present in mature HIV virions^ref, GP160 proteins and antibodies against these proteins should be absent not only from the Western blot assays but also in most cases from the serum of HIV-infected patients. The time course for such cross-reactivity remains uncertain (Western blot reversed to negativity after 1 month in a case report). Screening algotirhms should call for a nucleic acid amplification test instead of Western blot to confirm ELISA results^ref
Before highly active antiretroviral therapy (HAART) was introduced, the advantages to infected individuals of knowing their HIV status were minimal, and counselling before HIV testing was the recommended practice^ref. This usually limited testing, by relying on people who were obviously at risk presenting themselves for testing. Such groups included injecting drug users and men who have sex with men and their sexual contacts. Targeting of these groups will become an increasingly less useful concept as HIV continues to spread into the population that is conventionally not at risk. Do we need to reconsider if routine voluntary counselling and testing is appropriate today? Since 1991 heterosexual transmission of HIV has been the most common mode of transmission in the United Kingdom. Currently, nearly half of those infected heterosexually and a quarter of infected men who have sex with men in the United Kingdom are undiagnosed^ref. A quarter of newly diagnosed patients in the United Kingdom in 2002 were diagnosed late with serious immunosuppression.3 Unless further initiatives are undertaken the epidemic will worsen. Possible initiatives would be to lower thresholds for HIV testing by reducing the emphasis on pre-test counselling. Reasons for low HIV testing rates and thus low detection rates include concerns about confidentiality, legal and insurance issues, self perceptions of low risk in those who would test positive, denial, dislike of counselling, and wishing to avoid anxiety when waiting for results^{ref1, ref2}. Fear and denial are the commonest obstacles to HIV testing among those acknowledging that they have been at risk^ref. Additionally doctors' awareness of the effectiveness of early interventions is low and they may not encourage HIV testing^ref1,ref2. The most common reason, however, is lack of time for pre-test counselling, even in genitourinary medicine clinics^ref. Average times for counselling are > 21 minutes with 18% of people requiring 2 sessions^ref. Low detection rates imply longer duration of infections, which imply increased risk of HIV transmission. In an unpublished study, 70 randomly selected, HIV positive patients attending our centres were estimated to have been infected for a mean of 8.5 years. In that study, for only 56% had doctors broached HIV testing, only 6% of patients had ever declined HIV testing, and 46% of those who were HIV positive reported that their explicit consent to testing should not have been needed. Such results need to be replicated, but implications are clear. Lowering the threshold for HIV testing will lead to early diagnosis and treatment of infected individuals, which may prevent the development of AIDS and the transmission of infection^{ref1, ref2}. What is the role of voluntary counselling and testing? Voluntary counselling and testing has been accepted practice for more than 10 years. Uptake of voluntary counselling and testing, however, has been poor, even in those with high risk sexual activities. Sizeable proportions of infected people never attend genitourinary medicine clinics for voluntary counselling and testing even if referred. In addition, it seems that pre-test counselling is, on balance, not dramatically effective in reducing high risk sexual activity^ref. Many HIV infected individuals receive medical attention before they are diagnosed and opportunities for testing may have been discouraged by the "need" to perform or organise voluntary counselling and testing. Such patients would include, for example, those with persisting lymphopenia, neutropenia, or thrombocytopenia. A routine approach to testing would almost certainly increase the number of early HIV diagnoses, which would then allow concentration on subsequent informed counselling and education of patients and their partners and possible reduction in spread of infection. HAART has rendered HIV similar to other serious diseases. HIV testing should be widely accepted, without conventional voluntary counselling and testing, as patients at risk of cancer do not receive voluntary counselling and testing before chest x rays, or patients with chest infections do not routinely receive voluntary counselling and testing before stains for acid fast bacilli on sputum are requested. The current combination of reluctance of busy doctors to initiate pre-test counselling and denial by patients has resulted in late diagnosis and ongoing spread of infection. We propose that if a patient freely consents to be investigated, a doctor can initiate tests aimed at excluding serious diseases without an in depth discussion of all possible results, provided that the test result, positive or negative, should benefit the patient. Routine voluntary counselling and testing was appropriate to the 1980s. Times have changed. The benefits of early diagnosis of HIV are multiple. HIV testing should now not be accorded any special status. Doctors should now undertake the test by using the same approach as used in any other test with serious implications^ref
Treatment : despite the myriad abnormalities of immune function seen at all stages of HIV infection, reflected by both qualitative and quantitative T-cell, B-cell, and monocyte alterations, depletion of peripheral CD4⁺ helper-inducer T lymphocytes remains the best surrogate marker for clinical progression of HIV disease. As a consequence, antiretroviral therapy is used in HIV-seropositive, asymptomatic persons with CD4 counts < 500/ml and, in certain instances, in persons with counts < 700/ml, and prophylaxis against opportunistic infections is recommended when CD4 counts decrease to < 200/ml (Collier AC. Antiretroviral therapies. Infect Med. 1992; (Suppl 1): 11-9). In many situations the rate of decline in CD4 count, perhaps reflective of the phenotype of the predominant HIV isolate in a given person, is more predictive of advancing disease than is the absolute count^ref
• chemotherapy :
• HAART
• inhibitors of binding to CCR5 (maraviroc)
• inhibitors of gp41 (enfuvirtide)
• (aspartate) proteases inhibitors (PI) (-navir)
• integrase inhibitors (-gravir)
• RT inhibitors
• NRTI (-vudine)
  
• NNRTI (efavirenz, nevirapine)
  

In 2004 there are 6 million people living with HIV/AIDS in developing countries that urgently need access to antiretroviral treatment (ART), but only 400,000 have this access. A year's supply of a brand-name cocktail therapy for HIV/AIDS costs 562 US$, while the generic version costs 140 US$. The average annual salary in Botswana, where 38.8% of adult population is infected, is 3,440 US$. HIV sanctuaries are CD4⁺ resting T-lymphocytes (t_1/2= 8.5 days; activable by administering IL-2), macrophages (t_1/2 = 14 days), microglial cells and Langerhans cells. Therapy endpoint is to obtain [vRNA] < 5,000 / mL. Antigenic drift may create up to 15 different quasi-species in the same individual. The theory that structured treatment interruptions (STI) / ‘pulsing’ HAART, in chronically infected HIV-positive patients, apart from giving the patients a break from the side effects of drugs, allows the virus to mutate back to a form that is more susceptible to therapy has been discredited by the Swiss-Spanish Intermittent Treatment Trial (SSITT). The "drug holiday" could actually be detrimental, causing more frequen progression of disease and speeding up the attack on the immune system. However this study only included patients in whom HIV was detectable in the blood and the virus had already become resistant to drugs, and did not apply to individuals who are being successfully treated with HAART. Monitoring blood for cell counts or viral levels is essential to check that patients are taking their medicines, or to ensure that the virus has not become resistant to the drugs given, but patients in Africa, for example, often miss out on essential blood-cell monitoring because it requires fresh, refrigerated blood and expensive FACS machines. A new cheaper approach uses ELISA of dried whole blood spots to measure CD4⁺ lymphocyte counts in HIV-1-infected patients^ref. Through week 48, the combination of tenofovir DF and emtricitabine plus efavirenz fulfilled the criteria for noninferiority to a fixed dose of zidovudine and lamivudine plus efavirenz and proved superior in terms of virologic suppression, CD4⁺ lymphocyte response, and adverse events resulting in discontinuation of the study drugs^ref. In a RCT in Abidjan, Côte d'Ivoire, patients on CD4-guided HAART (CD4GT) with interruption and reintroduction thresholds at 350 and 250 cells/ml, respectively had severe morbidity rates 2.5-fold higher than those on CT. This difference was mainly due to high rates of common diseases in patients with CD4 count 200–500/ml^ref. HIV-infected patients fail to fully recover cell-mediated immunity despite HAART. To identify regulatory factors, the phenotype and function of in vitro CMV-stimulated T cells from HAART recipients were studied. CFSE-measured proliferation showed CD4⁺ and CD8⁺ cells dividing in CMV-stimulated cultures. Compared with healthy controls, CMV-stimulated lymphocytes from HAART recipients had lower ³H-thymidine incorporation; lower IFN-g and TNF-a production; higher CD4⁺CD27^-CD28^- and CD8⁺CD27^-CD28^- frequencies; lower CD4⁺CD25^hi; and higher FoxP3 expression in CD8⁺CD25^hi cells. CMV-specific proliferation correlated with higher IFN-g, TNF-a and IL10 levels and higher CD4⁺perforin⁺ and CD8⁺perforin⁺ frequencies. Decreased proliferation correlated with higher CD4⁺CD27^-CD28^- frequencies and TGF-b₁ production, which also correlated with each other. Anti-TGF-b₁ neutralizing antibodies restored CMV-specific proliferation in a dose-dependent fashion. In HIV-infected subjects, decreased proliferation correlated with higher CMV-stimulated CD8⁺CD25^hi frequencies and their FoxP3 expression. FoxP3- and TGF-b₁-expressing regulatory T cells contribute to decreased immunity in HAART recipients^ref. T-cell recovery after HAART in HIV-reconstituting-adults could be the consequence of antigen-independent peripheral T-cell expansion while in HIV-reconstituting-children thymic output could play a predominant role in immune reconstitution^ref. Immunological follow-up was performed in 45 early chronical HIV-1-infected patients during short STI cycles during the first 12 weeks after the definitive interruption of HAART (DTI) and, thereafter, until VL reached a plateau. During STI cycles, CD8⁺, CD8⁺, CD28⁺, activation markers and naive CD4⁺ T cells increased significantly (p < 0.0001), while both naive CD8⁺ and memory CD4⁺ T cells decreased. During DTI, CD8⁺ CD28⁺ T cells fell and CD4⁺ naive T cells stabilized and the rest of the T cell subsets presented changes similar to those during STI cycles. Despite a transient increase in LPR to recall antigens and HIV proteins during STI cycles, LPR to polyclonal stimuli and pathogens decreased over the study. Differences in T cell subset dynamics and LPR observed throughout the study suggest that multiple exposures to low levels of antigen could improve the immune system, mainly by driving T cell maturation. Conversely, higher and longer viral replication after cessation of HAART overwhelms the immune system. These data may help to guide future immune-based therapies^ref. Initial treatment with either NRTI+NNRTI or NRTI+PI regimens, but not NRTI+NNRTI+PI because of toxic effects, is a good strategy for long-term antiretroviral management in treatment-naive patients with HIV^ref.

• PEGylated rIFN-a_2b
• glycyrrhizin
• minocycline : in an experimental SIV model of HIV CNS disease, it reduced the severity of encephalitis, suppressed viral load in the brain, and decreased the expression of CNS inflammatory markers. In vitro, minocycline inhibited SIV and HIV replication^ref.
• SH, a herbal formula, as proven effective in 89% of HIV-1 patients in a recent clinical trial
• a 1-month course of HMG-CoA reductase inhibitors treatment caused the virus levels of human patients to drop by up to 20-fold. Levels began to rise when patients stopped taking the drug. When mice, injected with HIV-infected human cells, were given the drugs, their virus levels fell, in some cases to undetectable levels. Statins could also prove safer than antiretrovirals. HAART can trigger serious side-effects, such as liver damage, but statins are relatively free of such problems. Statins could also be used preventatively : WBCs taken from patients on statins are less likely to succumb to HIV infection^ref.
• daily dose of low-cost supplements of vitamins B, C and E reduces chances of going on to the later stages of HIV infection and of dying during a 6-year period by 30%, and stomatitis, rashes or fatigue in pregnant women when compared to the placebo group. They also induce higher TLCs and much lower levels of the AIDS virus. Costing around $15 a person each year, this would be a relatively cheap way to improve their QOL. The supplements could also postpone the point at which the disease worsens and patients need to be placed on antiretroviral therapy, which is more potent but costs around $300 to $400 for each patient annually (patients are not usually placed on antiretroviral drugs until the disease worsens because of their side-effects). Supplements are likely to have the biggest impact on HIV in the developing world, where poor nutrition is widespread : it is too early to say whether they will also benefit patients in the developed world, who probably already have good diets or whether they will have the same impact on men as women. Adding a vitamin A supplement to the multivitamin appeared to cut its beneficial effect
• HIV kills around 1,300 children daily. Many of them die from routine childhood bacterial infections, which overwhelm an immune system that has been hobbled by the virus. Co-trimoxazole, which costs a few pennies, reduces the death rate by 43% in children aged between 1 and 14, in Zambia. Co-trimoxazole is already a first line of defence against HIV-related infections, but the WHO currently recommends that only certain children should receive it, such as weeks-old babies whose mothers carry the virus and older children whose levels of WBCs are flagging. Now the WHO is revising these guidelines to recommend that the drug should be prescribed universally for African children showing any symptom of HIV infection. Widespread use of the antibiotic raises concerns that bacteria might acquire resistance to the drug. But the new trial was carried out in a region where antibiotic resistance to co-trimoxazole is already common, and the drug still worked, suggesting that enough susceptible bacteria remain for the drug to have an effect. Previously, medical workers have been dubious that it would work in such regions, so this result may help make a case for wider use of the antibiotic in adults too. The antibiotic should not, however, be seen as a substitute for HAART in children, which can cut the death rate by as much as 80%, but these medicines cost at least a few hundred dollars a year per person and are not yet widely used in African children.
• several genes that encode proteasome subunits and histone deacetylases are upregulated before lytic induction in HIV-1 latently infected cells, and other genes are downregulated, including EGR1 (which is involved in cell-cycle regulation), CDC42 (a RHO-family GTPase) and the tyrosine kinase LYN. Treating latently infected cells with a proteasome inhibitor or an EGR1 activator induced dose-dependent increases in p24 expression, showing that viral reactivation had occurred^ref— although the exact mechanisms by which these molecules end latency needs further study. The ability to drive HIV out of latency into lytic replication means that the virus could be susceptible to antiretroviral drugs, indicating that it might be possible to considerably reduce viral reservoirs^ref.
• nandrolone decanoate is superior to placebo and not significantly different from a FDA-approved regimen of rhGH in improving lean body mass in HIV-infected men with mild to moderate weight loss^ref
10% who test positive for HIV in Europe and USA is infected with a virus that is already resistant to drugs : resistant viruses are thought to be less infectious, but they can be passed on to some extent. It has been generally thought that resistance develops when patients take their HIV drugs irregularly (that is why some doctors deny anti-retrovirals to patients who are unlikely to take their drugs properly), allowing the virus to survive and adapt, but HIV patients who took 80% or more of their pills during a 1-year follow-up were twice as likely to be carrying a new mutated form of the virus compared to patients who took < 40% of their drugs. But this does not mean patients should take less of their drugs to avoid creating resistance : many patients with excellent, even perfect pill-taking are living longer with resistant virus than those who do not take medication to select for resistant virus.
A virulent strain of HIV that is resistant to 3 of the 4 classes of antiviral drugs (3-DCR HIV-1 : NRTI, NNRTI, and protease inhibitors) and progresses from infection to full-blown AIDS within 2-3 months, and at most 20 months (vs. a median of 8-10 years in the general population)^ref, was identified for the first time in a 46-years old New York City man who reported multiple male sex partners and unprotected receptive and inserptive anal intercourse, often while using crystal methamphetamine, first diagnosed in December 2004, who had no previous antiviral treatment^{ref1, ref2, ref3}. The case was in the top 0.5% in terms of rapidity of disease if 12 months was assumed as the duration of his infection. Viruses usually become less virulent when they acquire drug resistance : however, the replication capacity of the patient's HIV-1 was 136% in comparison with a median of 100% derived from a large number of wild-type viruses. This indicated that, despite its multidrug resistance, the virus replicated as well as most wild-type, drug-susceptible viruses. 10-20% of newly infected patients show resistance to a single antiviral drug. Viral sequence analysis indicated that the patient's virus was subtype B, and the relative homogeneity of the viral population was consistent with early HIV-1 infection. Phylogenetic analysis of a nucleotide sequence from the viral pol gene and from 30 newly infected individuals and 5 reference HIV-1 strains showed that the viral sequence of the new case was unique. No match was found in the center's sequence database. Because of its unique features, this pol sequence is now being compared with those in the database at the Los Alamos National Laboratory and in various commercial laboratories with the hope of finding a closely related HIV-1 that might provide an epidemiological link to this case. Genotypic analysis of the viral polymerase (pol) gene predicted that the patient's virus was resistant to most agents in 3 classes of ARVs: nucleoside or nucleotide analogue reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. Phenotypic drug-resistance testing indicated that the strain was susceptible to enfuvirtide and efavirenz. The virus was subtype B; the viral population was relatively homogeneous, with an average intrasample diversity for the p17 and V3 regions ranging from 0.4% to 1.7%. The virus was dual tropic and had replication capacity 36% greater than wild-type HIV strains. The patient tested negative for all known genetic host-susceptibility factors associated with rapid AIDS progression (e.g., presence of D32 homo- or heterozygosity, HLA A-B-C homozygosity, or specific Class I and Class II alleles). Resistance to > 1 drug usually develops over the course of several years of drug therapy because of the virus's ability to mutate. The New York man, who had no previous antiviral treatment, apparently was infected with a virus strain resistant to 3 classes of drugs from the start. Treatment options for the patient are limited: enfuvirtide and efavirenz are the only 2 antiretroviral drugs that can provide full activity against his virus. He has been started on a multidrug regimen, including enfuvirtide and efavirenz. Tracing of his sexual contacts has also begun. > 88,000 New Yorkers are known to be living with HIV/AIDS, and an estimated 20,000 more are believed to be living with HIV/AIDS and don't know it. In 2001 research workers in Dr Julio Montaner's group at the St Paul's Hospital and the University of British Columbia documented about a half-dozen cases of newly infected people whose strain of the virus is resistant to all 3 classes of anti-HIV drugs. It is common for AIDS patients to develop a resistance to some of the drugs they are taking, and 5 to 10% of new infections in the US involve a form of HIV resistant to some types of drugs used in treatment of AIDS. But there had been only a handful of reported cases in the world in which a person was newly infected with a type of HIV resistant to all 3 drug classes. In most of those cases, it was concluded at the time that in becoming triple drug-resistant, the virus had mutated in a way that made it less effective and less dangerous. The prevalence of transmitted HIV-1 drug resistance in the UK and the rest of Europe is assessed by surveillance of resistance in drug-naive individuals, and also in those individuals with recent infection, which is more comparable to the case described above. The UK HIV Resistance Database recorded a prevalence of any form of transmitted resistance of 18% within 2410 drug-naive individuals studied between 1996 and 2003, with 3% infected with 3-class resistant virus in 2002^ref. A similar data set from the Europe-wide CATCH study reported 10% (of a population of 1633) with any form of resistance between 1998 and 2002^ref. The largest data set from individuals with recent infection (thus allowing more accurate estimation of time trends for transmitted resistance) comes from the Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE), a large collaboration of seroconverter cohort data. Of 453 such individuals known to have been infected from 1987 to 2003, 12% had many form of resistance at diagnosis, with a peak of 19% in 1999. Only 0.5% were infected with 3-class resistant HIV (B Masquelier, et al. Changes in Prevalence and Characteristics of Transmitted Resistance over Time among European Seroconverter Cohort. Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; 2004 Feb 8-11; San Francisco, California, USA. Abstract 683). Since such cohorts allow follow-up of recruited individuals with a known time of infection, it is possible to explore the impact of transmitted resistance in the absence of therapy on CD4 decline, as a surrogate for disease progression. Such analysis of the UK Register of HIV Seroconverters over a 5 year follow-up period showed no difference in disease progression between those infected with resistant virus and those without^ref. This suggests that the rapid progression in the recent New York case was not necessarily due to the resistance pattern of the infecting virus strain. Taken together, these data sets show that transmission of drug resistance is evident in the UK and Europe as a whole. Although infection with such strains will compromise response to first line anti-retroviral therapy, there is little evidence to date, that such transmission is itself associated with increased pathogenicity or faster disease progression. Nevertheless, there exists a myriad of forms of HIV resistance. The possibility that particular resistant variants, currently at low frequency in the population, are more transmissible than others, or are more damaging cannot be excluded. In view of the ongoing transmission of HIV within Europe, such a possibility must be considered^ref. It is important to maintain large-scale population-based surveillance of transmitted resistant viruses. In particular, linking such data to clinical cohort follow-up will be essential for the early detection of viruses that respond poorly to anti-retroviral therapy and/or cause rapid disease progression^ref. The original source of the infection is a patient in Connecticut who infected the New York man during anonymous rectal intercourse at a sex club in the city on 22 Oct 2004.  Within 3 months, the New York man was diagnosed with HIV, and his CD4  blood-cell count had been  reduced to double digits. The patient, identified as CT01, is the so-called "Patient Zero" --- the source of the New York man's infection. The new HIV strain appeared to be multi-drug resistant, but the alarm may have been overblown, because his patient now has a stable infection that is being controlled by 2 drugs. We want to emphasize that our patient is not rapidly progressing. Nor is that patient's life partner, who is also infected with a similarly highly resistant strain, rapidly progressing. Even though New York health authorities said the strain was unknown, Blick said he knew the source was his patient just a few days later. He said he had received an urgent call shortly after the alarm was sounded from Quest/Nichols laboratory in San Juan Capistrano, Calif. Their HIV database had produced a 99.5% match between the New York man and one of Blick's patients, CT01. Blick later received another call from the lab that there was a 98.5% match with CT01's partner, CT02.  When an HIV strain is only about 1% different from another, they are usually almost identical. HIV mutates so rapidly that 100% identical strains are uncommon if the patients are tested at different times. Through interviews with his patients and New York authorities, Blick put together the following scenario: On 20 Oct 2004, CT01 provided blood samples that indicated a detectable viral load. The patient told Blick he had missed a few doses of Fuzeon, an injected  drug known generically as enfuvirtide. Fuzeon, which prevents entry of HIV into cells, is one of 2 drugs the 52-year-old man -- who has a long history of HIV infection -- can still take because his viral strain is resistant to all other medications. 2 days after visiting the doctor, CT01 and  CT02 traveled to New York to engage in sex at a club. They thought all the people at the club were HIV⁺. My patient is devastated that he infected the New York man, whom he thought was already HIV⁺. At the club, CT01 had insertive anal intercourse with ejaculation into the New York man. CT02, a 41-year-old man who has lived with CT01 for 12 years, had insertive anal intercourse without ejaculation with the same man. 3 months later, the New York man showed symptoms of recent infection and was seen at the  Aaron Diamond AIDS Research Center. When his CD4 count was measured at 88 cells, the alarm was sounded. The New York man's use of crystal methamphetamine and highly promiscuous lifestyle may be more of a factor in his low CD4 count than the strain of virus. The New York man had sex with at least 10 other partners before he discovered he was infected. Blick said it is possible other infections with that strain may show up later when those men are tested -- if they became infected. 3 other patients with similar risk factors who engaged in high-risk sexual activity at the same time and in the same venues as the index patient and who were infected with a genotypically homologous strain of HIV^ref. As of 21 Jul 2006, the index patient and 2 of the patients with matching genotypes were clinically stable and responding to ARVs. Nonetheless, ongoing surveys of a wider section of sexually active males indicate that as many as 15% of patients are infected with an HIV strain that has mutations associated with resistance to anti-retroviral drugs and that 3.2% have mutations associated with resistance to 2 or more classes of such agents.
Web resources : Geno2pheno: Estimating phenotypic drug resistance from HIV-1 genotypes
• gene therapy
• immunotherapy
• therapeutic vaccines
• anti-CTLA-4 mAb
• broadly neutralizing mAb (also called superantibodies) to HIV-1 are rare but invaluable for vaccine design. 4E10, isolated from an HIV-positive individual about a decade ago, is the broadest neutralizing antibody known (nearly 100 different viral strains of HIV from all over the world) and recognizes a contiguous and highly conserved epitope in the membrane-proximal region of gp41. The crystal structure of Fab 4E10 was determined at 2.2 Å resolution in complex with a 13-residue peptide containing the gp41 core epitope (NWFDIT). The bound peptide adopts a helical conformation in which the key contact residues, TrpP672, PheP673, IleP675, and ThrP676, map to one face of the helix. The peptide binds in a hydrophobic pocket that may emulate its potential interaction with the host cell membrane. The long CDR H3 of the antibody extends beyond the bound peptide in an orientation that suggests that its apex could contact the viral membrane when 4E10 is bound to its membrane-proximal epitope. These structural insights should assist in the design of immunogens to elicit 4E10-like neutralizing responses^ref.
Prophylaxis :
• the global spread of the HIV-1 has recently been driven by a dramatic increase in heterosexual transmission, which is the predominant route of transmission in developing countries
• monogamy : ecological and epidemiological evidence from generalised epidemics points to partner reduction as the primary behavioural factor explaining declines in HIV prevalence, which we now see in several African countries
• male and female condoms can lower the risk of transmission^{ref1, ref2}, but universal acceptance of these mechanical barrier methods may be difficult to achieve^{ref1, ref2}. Increased condom availability or use has not shown a similar pattern of association with prevalence decline across multiple generalised epidemics^{ref1, ref2}. Could condom promotion exacerbate epidemics? The phenomenon of risk compensation—engaging in higher-risk behaviours because risk reduction technology conveys a greater sense of safety than warranted—could account for higher infection rates,^ref and has been suggested by at least one randomised, controlled study, which found that “gains in condom use seem to have been off set by increases in the number of sex partners^ref.” The root of the problem is that people do not use condoms consistently, no matter how they are promoted. A little bit of condom use

might be like a little bit of antibiotic use—not ultimately helpful.
• broad-spectrum, low-toxicity, female-controlled, low-cost microbicides for topical vaginal use against infection by HIV-1 and other sexually transmitted disease (STD) pathogens
• Carraguard^®, made from a seaweed extract, gums up the surface of virus and vaginal cells to create a physical barrier against infection
• Buffergel^® increases acidity to oust the virus
• nonoxynol-9 (N-9), a spermicidal ingredient in common over-the-counter contraceptive products, has been tested as a microbicide in phase III clinical trials. However, its future as a microbicide is in question, due to its dose-dependent toxicity^{ref1, ref2}, proinflammatory effects^ref, and apparent lack of in vivo efficacy against HIV-1 transmission^{ref1, ref2}. It was found in 2000 to actually increase the HIV infection rate
• genital cleansing with soap and water after intercourse can prevent HIV infection : 2 or 6' of exposure to a commercial bar soap (Ivory; Johnson & Johnson) and water decreased the infectivity of HIV by more than 1000-fold in cervicovaginal lavage (CVL) fluid. When the virus was in a CVL-seminal fluid mixture, a stronger concentration of soap in water was required to reduce viral infectivity by 30-fold. Soap and water should not be used as a douche to eliminate HIV from the vagina because this method has not been tested yet and soap can have adverse effects, including disrupting the lining of vagina that might actually make it more susceptible to infection, and altering the normal population of vaginal microbes that can protect against other infections.
• circumcised men could be over 6 times less likely than uncircumcised men to acquire HIV-1 infection (RR = 0.15), but they have no protective effect against HSV-2, syphilis, or gonorrhoea^{ref1, ref2}. The explanation for this decreased risk in circumcised men is likely to be biological rather than behavioural^ref. Some investigators have argued that circumcision is simply an epidemiological marker of reduced behaviours related to risk of HIV-1 infection, including religious or cultural factors^ref. Others have suggested that circumcision reduces the risk of other sexually transmitted diseases associated with genital ulceration or mucosal inflammation, which secondarily reduces the risk of HIV-1. Circumcision has also been postulated to reduce the risk of HIV-1 by removing a possible entry point of the virus--the thinly keratinised mucosa of the inner foreskin and its HIV target cells^ref. 22 of the 1,393 circumcised men in the study contracted HIV in Kenya, compared to 47 of the 1,391 uncircumcised men. In other words, circumcised men had 53% fewer HIV infections than uncircumcised men^ref
• b12 mAb
• subunit vaccine trials : in February 2003, after more than a decade of work, a team of scientists representing the biotechnology company VaxGen announced the results of the first phase 3 trial to test the efficacy of a vaccine against HIV. Despite the highest of hopes, their product, AIDSVax — which contains a synthetic monomeric glycoprotein based on gp120 — did not prevent HIV infection in the study cohort as a whole. It was a frustrating setback for HIV-vaccine research, a field that has endured a Sisyphean onslaught of disappointments. But if the virus that causes AIDS is persistent, the vaccine researchers are no less so. Indeed, on July 14, 2005, the NIAID announced a grant of > $300 million for a new Center for HIV/AIDS Vaccine Immunology. The center aims to address key immunology roadblocks to HIV-vaccine development and to design, develop, and test novel vaccine candidates. As of this writing, 2 phase 2 trials that are testing therapeutic HIV vaccines are under way — these vaccines are designed not to prevent infection but, rather, by stimulating T lymphocytes that can identify and kill HIV-infected cells, to prevent or limit viral replication and delay disease progression. Although experts have not given up the ultimate goal of a preventive vaccine, they are hopeful that a therapeutic vaccine will, at least, help stem the devastating tide of disease, disability, and death from AIDS. Because the AIDS epidemic has occurred at a time when medical science is progressing at a rapid clip, unrealistic expectations or promises about its conquest have played a supporting role in this drama since the epidemic's earliest days. Historians have pinpointed April 23, 1984, as the moment of the most wildly optimistic prediction about an AIDS vaccine. At a press conference in Washington, D.C., at which the identification of the virus we now call HIV was announced, Margaret Heckler, the Secretary of Health and Human Services, proclaimed that a preventive vaccine would be ready for testing within 2 years. Several scientists seated in the packed auditorium "blanched visibly" at Heckler's declaration. Their reaction was understandable. After all, it had taken 105 years to develop a vaccine for typhoid after the discovery of its microbiologic cause; the Haemophilus influenzae vaccine took 92 years; pertussis vaccine, 89 years; polio vaccine, 47 years; measles vaccine, 42 years; and HBV, 16 years. And so, after a mere 21 years, we continue to struggle to contain the pandemic of our age. This year, 34 candidate HIV vaccines are in the early phases of human clinical trials in 19 countries. But, as in 1984, a safe and effective preventive vaccine remains elusive. Some delay can justly be blamed on inadequate funding. In 2004, about $680 million, primarily from the public sector but in smaller amounts from the private sector and philanthropy, went toward the development of AIDS vaccines — < 1% of the total global spending on health-product research and development. During the past century especially, the major pharmaceutical companies have led the way in developing most vaccines. Yet when it comes to HIV, many of these companies have been slow to participate, in part because there is so much uncertainty about which approach is most promising and in part because the return on the massive investment required is likely to be small, especially as compared with the profits generated by blockbuster drugs such as statins or antidepressants. The mechanism of normal HIV infection is shown, along with the mechanisms of 3 types of potential vaccines: a subunit vaccine containing a synthetic protein from the CD4-binding site on the envelope of the virus, a naked DNA vaccine, and a recombinant vaccine with a bacterial or viral vector


A substantial proportion of the entire investment in AIDS vaccines comes from the NIH : NIH needs to overcome the scientific barriers to the point that leads industry to say we can afford to get involved. But . . . at the end of the day, NIH — and academe — must partner with industry. The government or universities do not manufacture vaccines, the pharmaceutical companies do. But even if we could vanquish the economic challenges, as well as the myriad cultural, social, and ethical problems that attend the development of any vaccine, there remains one Himalayan obstacle: the remarkable pathogenic power of HIV itself. Even now, scientists do not know the correlates of immune protection — the specific types of immune responses that an effective HIV vaccine must stimulate in order to prevent infection. Typically, successful immune responses against viral infections include humoral and cellular components. The humoral reaction yields virus-neutralizing antibodies that prevent viral particles from infecting new cells. The cellular response mobilizes specific CD8⁺ CTLs that target and kill cells that express viral antigens. Thus, an optimal HIV vaccine would elicit both types of responses. Unfortunately, HIV has a large menu of mechanisms that enable it to undermine immune responses. Of the 60-million-plus people who have been infected with it, there's not a single documented case of someone who has ultimately cleared the infection from his or her body. The initial infection wipes out specific immune responses, the virus permanently integrates into the host cell's chromosome and establishes what appears to be a permanent reservoir of infected cells, and . . . the antigens that induce broadly reactive neutralizing antibodies do not appear to present themselves in a way that allows the host to elicit a protective immune response. Moreover, the plasticity of the virus affords a steady stream of new variants by means of frequent mutation and, sometimes, recombination. 3 major groups of HIV have been identified to date, and these have been divided into 9 subtypes or clades. Consequently, any effort to create a vaccine must use the broadest possible range of HIV isolates from around the globe and will demand constant surveillance of the virus in ensuing years. Another vexing problem has to do with an evolving understanding of the routes of infection. Although many people become infected through the bloodstream, 90% of HIV infections are contracted through sexual transmission, with the virus crossing the mucosal tissues that line the genital tract, the rectum, and other body cavities. In April 2005, researchers reported that within days after macaques become infected with SIV, it destroys >50% of the memory CD4⁺ T cells in their guts^{ref1, ref2}. Studies of HIV infection in humans show a similar loss of intestinal memory CD4⁺CCR5⁺ T cells^{ref1, ref2}. These findings have convinced many AIDS experts that the mucosal immune system in general, and the intestinal immune system in particular, is the primary site of viral replication and persistence, as well as the site of the loss of CD4⁺ T cells. Although the role of the gut in the pathogenesis of the infection is still poorly understood, vaccine strategies that target this type of immunity may revolutionize HIV research and therapy. The gut is a major target for HIV in the first 2 weeks of infection, and we never see patients that early, making the concept of utilizing a therapeutic vaccine to stabilize or preserve immunity among HIV-infected persons difficult. During the mid-1980s, scientists identified GP120 on the envelope of the virus as the CD4-binding site, the region that attaches to human cells and facilitates the entry of HIV. As a result, much energy was spent on developing a vaccine based on genetically engineered GP120 and the larger glycoprotein GP160 to prevent the acquisition of infection. This was the approach taken by VaxGen in designing its vaccine. Although AIDSVax failed to provide protection against infection, its failure held some critical lessons: the structure of the HIV outer envelope differs from the structure of monomeric GP120, and the outer membrane of circulating HIV strains hides its epitopes in a variety of ways that genetically engineered GP120 proteins do not mimic successfully. The viral glycoproteins appear to have a protective shield, consisting of variable loop sequences and extensive N-linked glycosylation, that makes them relatively resistant to antibody neutralization. There is little evidence suggesting that these difficulties can be surmounted anytime soon. One of the sentinel observations of the natural history of HIV infection is that although some amount of T-cell depletion occurs in everyone who is infected, the virus is usually controlled for at least several years before it begins multiplying so rapidly that the immune system is destroyed. This temporary control corresponds to the presence of high numbers of T lymphocytes that can identify and kill HIV-infected cells. Such findings have led scientists to explore vaccines that stimulate these T cells, even though they do not prevent initial infection, in the hope of preventing or limiting viral replication and delaying disease progression. A number of such vaccines are now being tested. Some are live-vector vaccines containing a bacterium or virus that has been modified so that it does not cause disease but can transport a gene or genes into the body that will make one or more HIV proteins and confer some immunity. For example, a canarypox-vector vaccine containing HIV genes for both internal and envelope HIV proteins is being tested in a phase 3 trial in Thailand, but preliminary data on its immunogenicity are not encouraging. Another vaccine, now in the early stages of a "proof of concept," or phase 2B trial, contains replication-defective adenovirus type 5 that transmits the HIV genes gag, pol, and nef ; this vaccine looks far more promising. The trial, a collaboration between Merck and the NIAID-funded HIV Vaccine Trials Network, is being conducted under the direction of Dr. Corey. So far, only about 250 people have been enrolled in the USA, Peru, Brazil, and the Caribbean, but the target is 3000 volunteers. A different and propitious candidate, which is being developed at NIAID's Vaccine Research Center and is currently in a phase 2 trial, entails a combination approach: first, a vaccine is administered that uses naked DNA to prime an immune response to both internal HIV proteins and external HIV proteins; then, a booster shot involving an inactivated adenovirus vector is administered, which stimulates specific antibody responses to HIV envelope proteins and internal proteins. The hope is that this prime–boost strategy will be far more potent than the single adenovirus-vector or canarypox-vector vaccine and that it will address some of the challenges posed by the diversity of envelope proteins found among the various HIV isolates throughout the world^ref
• vaginal engineered Lactobacillus jensenii
• attenuated monkey virus quickly establishes durable immunity covering a wide range of antigenic variants. The protection seems to result from interference, as it cannot be passively transferred to normal monkeys by serum antibodies and seems not to involve immune cells. Reversion to virulence is, of course, a problem, but it is an approach worth pursuing.
• the University of Cape Town in South Africa has closed down the laboratories of one of its top scientists, who has been supporting an unproven herbal AIDS remedy. Girish Kotwal, head of medical virology at the university's Institute of Infectious Disease and Molecular Medicine, has been temporarily suspended from his research duties so the university can investigate his association with the plant extract Secomet V, which is manufactured and distributed by the Stellenbosch-based company Secomet. Secomet V has found a champion in Kotwal. But there have as yet been no clinical trials of the product. Kotwal has published some data from a trial with 4 individuals showing that the herbal extract, which comes as a Coca-Cola-coloured liquid, acts as a broad-spectrum inhibitor of viral entry. But Kotwal's work has also shown that it can be toxic to cells, at least in the test tube : much more testing is needed before the product should be used clinically. 2 AIDS patients in Stellenbosch died earlier in 2006 after sudden liver failure. Neither had been on antiretroviral drugs (ARVs), but both were taking Secomet V. Another of Hellstrom's patients, who has taken both ARVs and Secomet V, has been found to have abnormal liver enzymes. The product does not seem to be properly registered in the country as a herbal or complementary medicine, and some have raised potential ethical concerns about the university's sales royalty agreement with Secomet. This royalty agreement will be reviewed by the university on completion of their investigation. Kotwal was dealing with Secomet in a personal capacity, and has said that his behaviour regarding the product is unacceptable. Certain allegations of possible professional misconduct in respect of Kotwal are under investigation. The preliminary investigation committee convened on Monday 3 July to decide what the charges against him will be. He has been temporarily suspended from his research duties, and his laboratory has been closed, pending the outcome of this. Secomet, meanwhile, continues to sell their product. Their website says that the herbal extract is not intended to diagnose, treat, cure or prevent any disease but adds that patients generally experience a lowering of viral load, which allows their CD4 count to stabilize and then to start improving. Secomet cannot trade making medicinal claims. The company's conduct will be discussed at an Medicines Control Council meeting on Friday 7 July when the matter will be put forward for further clarity and investigation.

Web resources : The Dream Centre
Post-exposure prophylaxis (PEP)
Experimental animal models : adding a number of human proteins to the surface of mouse (Mus musculus) cells allows HIV to infect them, while human p32 subunit of replication protein A entice the virus back out. Without p32 for example, incomplete copies of HIV's genetic material accumulate in the mouse cell's nucleus - a process called over-splicing. As the virus reproduces about 50-times less efficiently in mouse than in human cells, there is another human protein or factor that must be expressed to get full virus production in the mouse cells.
HIV-1-derived viruses are used as transfection vector.
For other hypotheses on AIDS aetiology see : Peter Duesberg, Virusmyth.
• human immunodeficiency virus type 2 (HIV-2) :
Epidemiology : jumped from reservoir sooty mangabey (Cercocebus atys) to people in Guinea-Bissau before 1940 and didn't become widespread during war of independence there between 1963 and 1974 because of use of non-sterile injections during the war, along with increased sexual activity. The first European cases of HIV-2 were Portuguese veterans who had served during that war. At least 6 independent transmissions of SIV to humans have been proposed. 2 subtypes of HIV-2 are recognised, but HIV-2 has diversified and spread to a lesser extent than HIV-1 and is still commonest in Western Africa (expecially Guinea Bissau), where it infects 1% of population..
Proteomics :
• it uses CD195 / CCR5 as coreceptor
• gp120 binds to CD209 / DC-SIGN
Pathogenesis : unlike HIV-1-infected people, most HIV-2-infected subjects maintain a healthy CD4⁺ T cell count and a strong HIV-specific CD4⁺ T cell response. To define the cellular immunological correlates of good prognosis in HIV-2 infection, a cross-sectional study of HIV Gag-specific T cell function was conducted in HIV-1- and HIV-2-infected Gambians. Using cytokine flow cytometry and lymphoproliferation assays, we show that HIV-specific CD4(+) T cells from HIV-2-infected individuals maintained proliferative capacity, were not terminally differentiated (CD57^-), and more frequently produced IFN-g or IL-2 than CD4⁺ T cells from HIV-1-infected donors. Polyfunctional (IFN-g⁺/IL-2⁺) HIV-specific CD4⁺ T cells were found exclusively in HIV-2⁺ donors. The disparity in CD4⁺ T cell responses between asymptomatic HIV-1- and HIV-2-infected subjects was not associated with differences in the proliferative capacity of HIV-specific CD8⁺ T cells. This study demonstrates that HIV-2-infected donors have a well-preserved and functionally heterogeneous HIV-specific memory CD4⁺ T cell response that is associated with delayed disease progression in the majority of infected people^ref.
=> slower disease progression, limited impact on the survival of the majority of infected adults, much lower horizontal and vertical transmission, similar target cells infectivity (DNA) but decreased rate of virus production (RNA) => low viremia, much slower decline in CD4 cell counts.
• human immunodeficiency virus type 3 (HIV-3)
• simian immunodeficiency virus (SIV)
Epidemiology : it emerged in chimpanzees (Pan spp.) apparently through a commingling of 2 monkey viruses from the red-capped mangabey (Cercocebus torquatus) and the greater spot-nosed monkey / white-nosed guenon (Cercopithecus nictitans). SIVs infect around 30 species of African monkey, causing inapparent infection in African green monkeys and a disease resembling AIDS in macaques; chimpanzees are the only apes known to be naturally infected. 10-15% of one Tanzanian chimp population carry SIV. This is far lower than its 50% prevalence in monkeys, but similar to the HIV rate in some west central African human populations, where the virus first emerged. Chimps are 98% genetically the same as humans, and they don't get sick from SIV. The OPV/AIDS theory holds that chimpanzees from the Kisangani (previously Stanleyville) area in the Democratic Republic of Congo that were purportedly used in the preparation of OPV transmitted a SIVcpz to humans. Evidence against this has been piling up, first with the absence of SIVcpz or chimpanzee DNA in old OPV stocks^ref and then with data suggesting HIV originated 30 years before the OPV trails (date of the last common ancestor of the main group of HIV-1 to be 1931 (1915-41))^ref. SIV strains in the chimpanzee populations claimed to be the origin of HIV-1 under the OPV theory is highly divergent from HIV-1, revealing that Kisangani chimpanzees were not the source SIVcpz that crossed over to humans^ref. SIV infection has now been reported in 26 different species of African non-human primates, many of which are hunted and sold as food.
Nigerian states disrupt campaign to eradicate polio^ref
Proteomics :
• gp120 : the crystal structure of SIV surface protein gp120 was solved before it binds to CD4^ref and once bound :


It also binds to CD209 / DC-SIGN
• it uses CD195 / CCR5 as coreceptor
Transmission : monkeys infected with SIV administered onto the cheek pouch of the rhesus macaque, likely coming into contact with the oral mucosa and tonsils before being swallowed. Likely sites of infection include oral and esophageal mucosa and the tonsils. Further examination of the digestive tract showed that SIV was not present in tissues below the esophagus until 4 days post-infection, indicating that the stomach acids probably prevented the virus from entering through the stomach or intestines. At 1 day following oral exposure, the first lymph nodes infected were closest to the head and neck. 4 days after infection, the virus could be detected in nearly all tissues. T-cells and macrophages likely play key roles in disseminating the virus. Because SIV spreads so rapidly throughout the bodies of infected monkeys, it may help to explain why antiviral therapies can effectively protect a monkey or HIV infection of humans only if they are given within hours of exposure to the virus.
Pathogenesis : antibody-dependent enhancement (ADE) of viral infection. Rapid, profound, and selective depletion of memory CD4+ T cells has now been confirmed to occur in SIV infected adult macaques and HIV infected humans. Within days of infection, marked depletion of memory CD4⁺ T cells occurs primarily in mucosal tissues, the major reservoir for memory CD4⁺ T cells in adults. However, HIV infection in neonates often results in higher viral loads and rapid disease progression, despite the paucity of memory CD4⁺ T cells in the peripheral blood. The immunophenotype of CD4⁺ T cells was examined in normal and SIV-infected neonatal macaques to determine the distribution of naive and memory T cell subsets in tissues. Similar to adults, neonates have abundant memory CD4⁺ T cells in the intestinal tract and spleen, and that these are selectively infected and depleted in primary SIV infection. Within 12 days of SIV infection, activated (CD69⁺), central memory (CD95⁺CD28⁺) CD4⁺ T cells are marked and persistently depleted in the intestine and other tissues of neonates compared to controls. The results indicate that "activated" central memory CD4⁺ T cells are the major target for early SIV infection and CD4⁺ T cell depletion in neonatal macaques^ref
Chimpanzees (Pan troglodytes troglodytes) from west central Africa are recognized as the reservoir of simian immunodeficiency viruses (SIVcpzPtt) that have crossed at least twice to humans: this resulted in the AIDS pandemic (from human immunodeficiency virus HIV-1 group M) in one instance and
infection of just a few individuals in Cameroon (by HIV-1 group N) in another. A third HIV-1 lineage (group O) from west central Africa (accounting for just 1% of current AIDS cases in Cameroon) also falls within the SIVcpzPtt radiation : in 2006 HIV-1 group O-like viruses were discovered in western lowland gorillas^ref, but it is still too early to say whether they are a reservoir species or merely a carrier of the virus.
Therapy : CD195 / CCR5 agonists have antiviral activity against SIVmac251 and SIVB670 replication in vivo, resulting in marked decrease in plasma viraemia, which is maintained by 50% of macaques. Vaginal administration of gel-formulated drug reduces the extent of viraemia after infection with SHIV-162P4, but is unable to prevent vaginal transmission^ref
unclassified Lentivirus
• Human lymphotropic virus type III
• people in Cameroon are showing up with symptoms of HIV infection, but, are testing negative for both HIV and SIV, suggesting that new strains of an HIV-like virus are circulating in wild
animals and infecting people who eat them

The world's largest donor for fighting AIDS is the USA, which spent $2.4 billion in 2004. But it is being pressured by conservative religious groups toward abstinence-only programs and away from vulnerable groups like prostitutes, homosexuals and drug addicts. Included in the U.S. contribution is some $450 million, or 1/3 of the budget of the Global Fund to Fight AIDS, Tuberculosis and Malaria -- a powerful independent organization of governments, business and private groups, first proposed by Annan 4 years ago. The new head of the group's policy and strategy committee is Randall Tobias, who runs the Bush administration's AIDS program. Some officials are worried that the fund will adopt U.S. positions, but others say such fears are groundless. Worldwide some $8 billion will be available in 2005 to implement programs in 135 low- and middle-income countries, a dramatic 23% increase over the previous year. Of this amount, rich countries have contributed some $6.7 billion, 6 times greater than the world spent in 2001

Web resources :

• AIDS Clinical Trials Information Service (ACTIS)
• aidsmap
• AIDScience
• Conferences
• AIDS Information and Research
• American Foundation for AIDS Research (AmFAR)
• Elizabeth Glaser Pediatric AIDS Foundation
• Antiretroviral drugs by NIH
• Apathy is lethal
• Center for HIV/AIDS Vaccine Immunology (CHAVI)
• Consortium to Respond Effectively to the AIDS-TB Epidemic (CREATE)
• Elton John AIDS Foundation (EJAF)
• Epidemiological data by CDC
• Full-text of original papers on AIDS
• HIV and AIDS Treatment Information Services (HIVATIS)
• HIV InSite
• HIV Medicine by Bernd Sebastian Kamps, Christian Hoffmann, and Wolfgang Preiser
• HIV Sequence Database
• Sequence Database
• Resistance Database
• Immunology Database
• Vaccine Trials Database
• HIV Vaccine Design and Development Teams (HVDDT)
• HIV Web Study
• Immunology and AIDS
• International HIV Treatment Access Coalition (ITAC)
• International AIDS Economic Network (IAEN)
• Johns Hopkins AIDS Service Page
• Monitoring the AIDS Pandemic (MAP)
• Stanford HIV RT and Protease Sequence Database
• Search for AIDS Related Information at NIH :


• The Body : AIDS and HIV information resource for non-specialists
• TheraSim CS-HIV is a simulation software system designed to help clinicians learn and keep up with the latest advances in the diagnosis and treatment of infectious diseases.  Interactive cases based on actual patient data enable individuals to work through realistic management scenarios and to receive feedback on patient care decisions.  The program also lets participants know how their decisions compare with those of others who have participated in the program. The World Health Organization estimates that 100,000 health care workers must be trained in 2005 alone to meet the needs of HIV/AIDS patients around the world.
• The Virtual Library - AIDS
• Therapeutics, Research, Education and AIDS Training (TREAT) in Asia
• UNAIDS
• WHO :
• HIV
• The 3 by 5 Initiative : the 2000 International AIDS Conference in Durban, South Africa, focused the world's attention on disparities between rich and poor countries with respect to access to antiretroviral drugs. At that time, an estimated 7000 people in Africa had access to effective combination antiretroviral regimens. Though the number exceeds 100,000 today, it is still a far cry from the 8 million who are thought to require such therapy. In response, in 2003, the World Health Organization (WHO) launched an ambitious program termed "3 by 5" in an attempt to treat at least 3 million infected people by the end of 2005^ref
• Usenet discussion groups
• bionet.molbio.hiv
• sci.med.aids
• www.hivaidsonline.com
• Journals :
• Journals AIDS Science and Vaccine Research

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