Primate lentivirus group : HIV-1, HIV-2

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 percent 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

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 TLR4

induces 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.
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.
dual-tropic / R5X4 strains use CXCR4 / CD184 / fusin / LESTR , CCR5 / CD195 and CCR2B as coreceptors

in vitro

^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.

CD209 / dendritic-cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) / CIRE

macrophage mannose receptor

langerin

⁺

^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

^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.
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

HIV-1 Rev binding protein (HRB)

HIV-1 rev binding protein 2 (HRB2)

Rev 34-50

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 CD3d e g, 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.
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

⁺

nevirapine

OraQuick test

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 GM₃antibodies 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

^ref

⁺

^ref

⁺

^ref

⁺

ICL

^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.

=> a chronic syndrome
CDC staging, 1987 :