HIV: Difference between revisions

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Human immunodeficiency virus (commonly known as HIV, and formerly known as HTLV-III and lymphadenopathy-associated virus^[1][2]) is a retrovirus that is the cause of the disease known as AIDS (Acquired Immunodeficiency Syndrome), a syndrome where the immune system begins to fail, leading to many life-threatening opportunistic infections.

HIV primarily infects vital components of the human immune system such as CD4⁺ T cells (directly and indirectly destroying them), macrophages and dendritic cells. As CD4⁺ T cells are required for proper functioning of the immune system, when enough of them have been destroyed by HIV it compromises the immune system, leading to AIDS. HIV also directly attacks organs such as the kidneys, heart and brain, leading to acute renal failure, cardiomyopathy, dementia and encephalopathy. Many of the problems faced by people infected with HIV result from failure of the immune system to protect from opportunistic infections and cancers.

Infection with HIV occurs after the transfer of blood, semen, vaginal fluid, or breast milk from an infected person to an uninfected one. Within these body fluids HIV is carried as a free virus and in infected CD4⁺ T cells, dendritic cells, and macrophages. The three major routes of transmission are sexual intercourse, sharing of contaminated needles used for intravenous drug delivery and transmission from an infected mother to her baby at birth or through breast milk. In the developed world transmission through the therapeutic use of infected blood or blood products has largely been eliminated where blood products are screened routinely for the presence of HIV.

Infection in humans is now pandemic. As of January 2006, the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) estimate that AIDS has killed more than 25 million people since it was first recognized on December 1, 1981, making it one of the most destructive pandemics in recorded history. In 2005 alone, AIDS claimed an estimated 2.4—3.3 million lives, of which more than 570,000 were children.^[3] A third of these deaths are occurring in sub-Saharan Africa, retarding economic growth by destroying human capital.^[4] Current estimates state that HIV is set to infect 90 million people in Africa, resulting in a minimum estimate of 18 million orphans.^[5] Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection, but routine access to antiretroviral medication is not available in all countries.^[6]

The AIDS epidemic was discovered June 5, 1981, when the U.S. Centers for Disease Control and Prevention reported a cluster of Pneumocystis carinii pneumonia (now classified as Pneumocystis jiroveci pneumonia) in five homosexual men in Los Angeles.^[7] Originally dubbed GRID, or Gay-Related Immune Deficiency, health authorities soon realized that nearly half of the people identified with the syndrome were not homosexual men. In 1982, the CDC introduced the term AIDS to describe the newly recognized syndrome, though it was still casually referred to as GRID.

In 1983, scientists led by Luc Montagnier at the Pasteur Institute in France first discovered the virus that causes AIDS.^[8] They called it lymphadenopathy-associated virus (LAV). A year later a team led by Robert Gallo of the United States confirmed the discovery of the virus, but they renamed it human T lymphotropic virus type III (HTLV-III).^[9] The dual discovery led to considerable scientific disagreement, and it was not until President Mitterrand of France and President Reagan of the USA met that the major issues were resolved. In 1986, both the French and the US names for the virus itself were dropped in favour of the new term, human immunodeficiency virus (HIV).^[2]

HIV was classified as a member of the genus lentivirus,^[10] part of the family of retroviridae.^[11] Lentiviruses have many common morphologies and biological properties. Many species are infected by lentiviruses, which are characteristically responsible for long duration illnesses associated with a long period of incubation.^[12] Lentiviruses are transmitted as single-stranded, positive-sense, enveloped RNA viruses. Upon infection of the target cell, the viral RNA genome is converted to double-stranded DNA by a virally encoded reverse transcriptase which is present in the virus particle. This viral DNA is then integrated into the cellular DNA by a virally encoded integrase so that replication using cellular machinery may take place. Once the virus enters the cell, two pathways are possible: either the virus becomes latent and the infected cell continues to function, or the virus becomes active and replicates, and a large number of virus particles are liberated which can infect other cells.

Two species of HIV infect humans: HIV-1 and HIV-2. HIV-1 is hypothesized to have originated in southern Cameroon after jumping from wild chimpanzees (Pan troglodytes troglodytes) to humans during the twentieth century.^[13][14] HIV-2 is hypothesized to have originated from the Sooty Mangabey (Cercocebus atys), an Old World monkey of Guinea-Bissau, Gabon, and Cameroon.^[15] HIV-1 is more virulent, more easily transmitted and is the cause of the majority of HIV infections globally, while HIV-2 is less easily transmitted and is largely confined to West Africa.^[15] HIV-1 is the virus that was initially discovered and termed LAV.

Three of the earliest known instances of HIV-1 infection are as follows:

1. A plasma sample taken in 1959 from an adult male living in what is now the Democratic Republic of Congo.^[16]
2. HIV found in tissue samples from a 15 year old African-American teenager who died in St. Louis in 1969.^[17]
3. HIV found in tissue samples from a Norwegian sailor who died around 1976.^[18]

Although a variety of theories exist explaining the transfer of HIV to humans, there is no widely accepted scientific consensus of any single hypothesis and the topic remains controversial. Freelance journalist Tom Curtis discussed one currently controversial possibility for the origin of HIV/AIDS in a 1992 Rolling Stone magazine article. He put forward what is now known as the OPV AIDS hypothesis, which suggests that AIDS was inadvertently caused in the late 1950s in the Belgian Congo by Hilary Koprowski's research into a polio vaccine.^[19] Although subsequently retracted due to libel issues surrounding its claims, the Rolling Stone article motivated another freelance journalist, Edward Hooper, to probe more deeply into this subject. Hooper's research resulted in his publishing a 1999 book, The River, in which he alleged that an experimental oral polio vaccine prepared using chimpanzee kidney tissue was the route through which simian immunodeficiency virus (SIV) crossed into humans to become HIV, thus starting the human AIDS pandemic.^[20]

For more details on this topic, see AIDS transmission and prevention

Since the beginning of the pandemic, three main transmission routes of HIV have been identified:

• Sexual route. The majority of HIV infections are acquired through unprotected sexual relations. Sexual transmission occurs when there is contact between sexual secretions of one partner with the rectal, genital or oral mucous membranes of another.
• Blood or blood product route. This transmission route can account for infections in intravenous drug users, hemophiliacs and recipients of blood transfusions (though most transfusions are checked for HIV) and blood products. It is also of concern for persons receiving medical care in regions where there is prevalent substandard hygiene in the use of injection equipment, such as the reuse of needles in Third World countries. Health care workers such as nurses, laboratory workers, and doctors, have also been infected, although this occurs more rarely. People who give and receive tattoos, piercings and scarification procedures can also be at risk of infection.
• Mother-to-child transmission (MTCT). The transmission of the virus from the mother to the child can occur in utero during the last weeks of pregnancy and at childbirth. In the absence of treatment, the transmission rate between the mother and child is 25%.^[23] However, where treatment is available, combined with the availability of Cesarian section, this has been reduced to 1%.^[23] Breast feeding also presents a risk of infection for the baby.

HIV has been found at low concentrations in the saliva, tears and urine of infected individuals, but the risk of transmission by these secretions is negligible. The use of physical barriers such as the latex condom is widely advocated to reduce the sexual transmission of HIV. Current research is clarifying the relationship between male circumcision and HIV in differing social and cultural contexts.^[29] Even though male circumcision may lead to a reduction of infection risk in heterosexual men by up to 60%,^[30] UNAIDS believes that it is premature to recommend male circumcision as part of HIV prevention programs.^[31] Moreover, South African medical experts are concerned that the repeated use of unsterilized blades in the ritual circumcision of adolescent boys may be spreading HIV.^[32]

HIV is different in structure from other retroviruses. It is about 120 nm in diameter (120 billionths of a meter; around 60 times smaller than a red blood cell) and roughly spherical.^[33]

It is composed of two copies of positive single-stranded RNA that codes for the virus's nine genes enclosed by a conical capsid composed of 2,000 copies of the viral protein, p24.^[34] The single-stranded RNA is tightly bound to nucleocapsid proteins, p7 and enzymes that are indispensable for the development of the virion such as reverse transcriptase, proteases and integrase. A matrix composed of an association of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle.^[34] This is, in turn, surrounded by the viral envelope which is composed of two layers of fatty molecules called phospholipids taken from the membrane of a human cell when a newly formed virus particle buds from the cell. Embedded in the viral envelope are proteins from the host cell, as well as 72 copies (on average) of a complex HIV protein that protrudes through the surface of the virus particle.^[34] This protein, known as Env, consists of a cap made of three molecules called glycoprotein (gp) 120, and a stem consisting of three gp41 molecules that anchor the structure in the viral envelope.^[35] This glycoprotein trimer enables the virus to attach to and fuse with target cells to initiate the infectious cycle.^[35] Both, especially gp120, have been considered as targets of future treatments or vaccines against HIV.^[36]

Of the nine genes that are encoded within the RNA genome, three of these genes, gag, pol, and env, contain information needed to make the structural proteins for new virus particles.^[34] env, for example, codes for a protein called gp160 that is broken down by a viral enzyme to form gp120 and gp41. The six remaining genes, tat, rev, nef, vif, vpr, and vpu, are regulatory genes that contain information necessary to produce proteins that control the ability of HIV to infect cells, produce new copies of virus (replicate), or cause disease.^[34] The protein encoded by nef, for instance, appears necessary for the virus to replicate efficiently, and the vpu-encoded protein influences the release of new virus particles from infected cells.^[34] The ends of each strand of HIV RNA contain an RNA sequence called the long terminal repeat (LTR). Regions in the LTR act as switches to control production of new viruses and can be triggered by proteins from either HIV or the host cell.^[34]

The term viral tropism refers to the cell type into which HIV may infect and replicate within. HIV can infect a variety of cells such as CD4⁺ T cells, macrophages, and microglial cells. HIV-1 entry to macrophages and CD4⁺ T cells is mediated not only through interaction of the virion envelope glycoproteins (gp120) with the CD4 molecule on the target cells but also with its chemokine coreceptors.^[35]

Macrophage (M-tropic) strains of HIV-1, or non-syncitia-inducing strains (NSI) use the β-chemokine receptor CCR5 for entry and are thus able to replicate in macrophages and CD4⁺ T cells.^[37] The normal ligands for this receptor, RANTES, macrophage inflammatory protein (MIP)-1-beta and MIP-1-alpha, are able to suppress HIV-1 infection in vitro. This CCR5 coreceptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype. Indeed, macrophages play a key role in several critical aspects of HIV disease. They appear to be the first cells infected by HIV and perhaps the very source of HIV production when CD4⁺ cells are markedly depleted in the patient. Macrophages and microglial cells are the cells infected by HIV in the central nervous system. In tonsils and adenoids of HIV-infected patients, macrophages fuse into multinucleated giant cells that produce copious amounts of virus.

T-tropic isolates, or syncitia-inducing (SI) strains replicate in primary CD4⁺ T cells as well as in macrophages and use the α-chemokine receptor, CXCR4, for entry.^[37][38][39] The α-chemokine, SDF-1, a ligand for CXCR4, suppresses replication of T-tropic HIV-1 isolates. It does this by down regulating the expression of CXCR4 on the surface of these cells. HIV that use only the CCR5 receptor are termed R5, those that only use CXCR4 are termed X4, and those that use both, X4R5. However, the use of coreceptor alone does not explain viral tropism, as not all R5 viruses are able to use CCR5 on macrophages for a productive infection^[37] and HIV can also infect a subtype of myeloid dendritic cells,^[40] which probably constitute a major reservoir that maintains infection when CD4⁺ T cell numbers have declined to extremely low levels.

Some people are resistant to certain strains of HIV.^[41] An example of this is people with the CCR5-Δ32 mutation; these people are resistant to infection with R5 virus as the mutation does not allow HIV to bind to this coreceptor, impeding its ability to infect the target cell.

Heterosexual intercourse is the major mode of HIV transmission. Both X4 and R5 HIV are present in the seminal fluid as free or cell associated particles which are passed from partner to partner where the virions can then infect numerous cellular targets and disseminate into the whole organism. However, a selection process has been shown to lead to a predominant transmission of the R5 virus through this pathway.^[42][43][44] The mechanism of this selective process is still under investigation, though recent data suggest that spermatozoa may selectively carry R5 HIV as they possess both CCR3 and CCR5 but not CXCR4 on their surface^[45] and that genital epithelial cells preferentially sequester X4 virus.^[46] In patients infected with subtype B HIV-1, there is often a co-receptor switch in late stage disease and T-tropic variants appear that can infect a variety of T cells via CXCR4.^[47] These variants then replicate more aggressively with heightened virulence that facilitates rapid T cell depletion, immune system collapse, and opportunistic infection that marks the advent of AIDS.^[48] Thus, during the course of infection, viral adaptation to the use of CXCR4 instead of CCR5 is often seen as a key step in the progression to AIDS. A number of studies with subtype B-infected individuals have determined that between 40 and 50% of AIDS patients can harbour viruses of the SI, and presumably the X4, phenotype.^[49][50]

HIV enters macrophages and CD4⁺ T cells by the adsorption of glycoproteins on its surface to receptors on the target cell followed by fusion of the viral envelope with the cell membrane and the release of the HIV capsid into the cell.^[51][52]

The interactions of the trimeric envelope complex (gp160 spike) and both CD4 and a chemokine receptor (generally either CCR5 or CXCR4 but others are known to interact) on the cell surface.^[51][52] The gp160 spike is composed of three transmembrane glycoproteins (gp41), which anchor the cluster to the virus, and three extracellular glycoproteins (gp120), which contain the binding domains for both CD4 and chemokine receptors.^[51][52] The first step in fusion involves the high-affinity attachment of the CD4 binding domains of gp120 to the N-terminal membrane-distal domains of CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine binding domains of gp120 and allowing them to interact with the target chemokine receptor.^[51][52] This allows for a more stable two-pronged attachment, which leads to the N-terminal fusion peptide gp41 to penetrate the cell membrane.^[51][52] Two heptad repeat sequences of gp41, HR1 and HR2, then interact, resulting in the collapse of the extracellular portion of gp41 forming a hairpin. This hairpin structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.^[51][52]

Once HIV has bound to the target cell, the HIV RNA and various enzymes, including but not limited to reverse transcriptase, integrase and protease, are injected into the cell.^[51]

HIV can infect dendritic cells (DCs) by the CD4-CCR5 route, but also by another route using mannose-specific C-type lectin receptors such as DC-SIGN.^[53] DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T cells once the virus has been captured in the mucosa by DCs.^[54]

Once the viral capsid has entered the cell, an enzyme called reverse transcriptase liberates the single-stranded (+)RNA from the attached viral proteins and copies it into a negatively sensed viral complementary DNA of 9 kb pairs (cDNA).^[55] This process of reverse transcription is extremely error prone and it is during this step that mutations (such as drug resistance) are likely to arise. The reverse transcriptase then makes a complementary DNA strand to form a double-stranded viral DNA intermediate (vDNA). This new vDNA is then transported into the cell nucleus. The integration of the proviral DNA into the host genome is carried out by another viral enzyme called integrase.^[55] This is called the latent stage of HIV infection.^[55] To actively produce virus, certain cellular transcription factors need to be present, the most important of which is NF-κB (NF kappa B), which is upregulated when the T cell becomes activated.^[56] This means that those cells most likely to be killed by HIV are in fact those currently fighting infection.

Initially the integrated provirus is copied to mRNA which is then spliced into smaller chunks. These small chunks produce the regulatory proteins Tat (which encourages new virus production) and Rev. As Rev accumulates it gradually starts to inhibit mRNA splicing.^[57] At this stage the structural proteins Gag and Env are produced from the full-length mRNA. Additionally the full-length RNA is actually the virus genome, so it binds to the Gag protein and is packaged into new virus particles.

HIV-1 and HIV-2 appear to package their RNA differently; HIV-1 will bind to any appropriate RNA whereas HIV-2 will preferentially bind to the mRNA which was used to create the Gag protein itself. This may mean that HIV-1 is better able to mutate (HIV-1 infection progresses to AIDS faster than HIV-2 infection and is responsible for the majority of global infections).

The final step of the viral cycle, assembly of new HIV-1 virions, begins at the plasma membrane of the host cell. The Env polyprotein (gp160) goes through the endoplasmic reticulum and is transported to the Golgi complex where it is cleaved by protease and processed into the two HIV envelope glycoproteins gp41 and gp120. These are transported to the plasma membrane of the host cell where gp41 anchors the gp120 to the membrane of the infected cell. The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell. Maturation either occurs in the forming bud or in the immature virion after it buds from the host cell. During maturation, HIV proteases (proteinases) cleave the polyproteins into individual functional HIV proteins and enzymes. The various structural components then assemble to produce a mature HIV virion.^[58] This step can be inhibited by drugs. The virus is then able to infect another cell.

File:Subtype.png

One of the major characteristics of HIV is its high genetic variability as a result of its fast replication cycle and the high error rate and recombinogenic properties of reverse transcriptase.^[59] This means that different genomic combinations may be generated within an individual who is infected by genetically different HIV strains. Recombination results when a cell is simultaneously infected by two different strains of HIV and one RNA transcript from two different viral strains are encapsidated into the same virion particle. This virion then infects a new cell where it undergoes replication. During this phase, the reverse transcriptase, by jumping back and forth between the two different RNA templates, will generate a newly synthesized retroviral DNA sequence that is a recombinant between the two parental genomes.^[59] This recombination is most obvious when it occurs between subtypes.^[59]

Three groups of HIV-1 have been identified on the basis of differences in env: M, N, and O.^[60] Group M is the most prevalent and is subdivided into eight subtypes (or clades), based on the whole genome, that are each geographically distinct.^[61] The most prevalent are subtypes B (found predominantly in North America and Europe), A and D (found predominantly in Africa), and C (found predominantly in Africa and Asia); these subtypes form branches in the phylogenetic tree representing the lineage of the M group of HIV-1. Coinfection with distinct subtypes gives rise to circulating recombinant forms (CRFs).

In 2000, the last year in which an analysis of global subtype prevalence was made, 47.2% of infections worldwide were of subtype C, 26.7% were of subtype A/CRF02_AG, 12.3% were of subtype B, 5.3% were of subtype D, 3.2% were of CRF_AE, and the remaining 5.3% were composed of other subtypes and CRFs.^[62] Most HIV-1 research is focused on subtype B, while few laboratories focus on the other subtypes.^[63]

Infection with HIV-1 is associated with a progressive decrease of the CD4⁺ T cell count and an increase in viral load. The rate by which the patient's CD4⁺ T cell count declines can be measured and is used to determine the stage of infection. High levels of HIV in the plasma is observed during all stages of infection range from just 50 to 11 million virions per mL.^[64]

There are four stages of HIV infection: primary infection (or viremia or acute infection) which progresses over time to clinical latency (where the virus is a provirus inside monocytes) and then to symptomatic HIV infection, and finally, AIDS which is identified on the basis of certain infections, an HIV test and a CD4⁺ T cell count.

Primary, or acute infection is a period of rapid viral replication that immediately follows the individual's exposure to HIV. During this period most individuals (80 to 90%) develop an acute syndrome characterised by flu-like symptoms of fever, malaise, lymphadenopathy, pharyngitis, headache, myalgia, and sometimes a rash.^[65] Within an average of three weeks after transmission of HIV-1, a broad HIV-1 specific immune response occurs that includes seroconversion. Because of the nonspecific nature of these illnesses, it is often not recognized as a sign of HIV infection. Even if patients go to their doctors or a hospital, they will often be misdiagnosed as having one of the more common infectious diseases with the same symptoms. These primary symptoms are not used as an indicator of HIV infection as they do not develop in all cases and because many are caused by other more common diseases. However, recognizing the syndrome is important because the patient is much more infectious during this period. At this stage, measuring the CD4⁺ T cell count is not a mechanism of detection as the it is still higher than 1000 cells per µL, well within the normal range.

A strong immune defense reduces the number of viral particles in the blood stream, marking the start of the infection's clinical latency stage. Clinical latency can vary between two weeks and 20 years. During this early phase of infection, HIV is active within lymphoid organs, where large amounts of virus become trapped in the follicular dendritic cells (FDC) network.^[66] The surrounding tissues that are rich in CD4⁺ T cells may also become infected, and viral particles accumulate both in infected cells and as free virus. Individuals who have entered into this phase are still infectious. The CD4⁺ T cell count is normally at or around 1000 cells per µL. During this time, CD4⁺ CD45RO⁺ T cells carry most of the proviral load.^[67]

The first symptoms of HIV infection often include moderate and unexplained weight loss, recurrent respiratory tract infections (such as sinusitis, bronchitis, otitis media, pharyngitis), herpes zoster and recurrent oral ulcerations.

With the progression of the illness, other symptoms may start to present. These include unexplained chronic diarrhoea and persistent fever (for longer than one month), severe weight loss (>10% of presumed or measured body weight), oral hairy leukoplakia and candidiasis and severe bacterial infections including pulmonary tuberculosis. It is during this period that the CD4⁺ T cells count starts to fall below 500 cells per µL.

For more details on this topic, see AIDS Diagnosis and AIDS Symptoms and Complications.

AIDS is the most severe manifestation of infection with HIV and occurs when the CD4⁺ T cell count drops to below 200 cells per µL. Typical symptoms are severe opportunistic infections, rare cancers, neurological complications, and malnutrition. These include:

• Kaposi's sarcoma - a cancer of the blood vessels that accounts for extensive "bruising" sometimes seen in AIDS patients. It is aggressive, and can attack the mouth, lymph nodes, and internal organs, which may include the lungs or gastrointestinal tract.
• Pneumocystis jiroveci pneumonia - a form of pneumonia caused by the yeast-like fungal microorganism Pneumocystis jiroveci (sometimes spelled jirovecii and formerly classified as Pneumocystis carinii).
• AIDS dementia complex - encephalopathy due to HIV-infected brain cells
• Toxoplasmosis, Progressive multifocal leukoencephalopathy, common bacterial infections (Salmonella, Shigella, Listeria, Campylobacter, or Escherichia coli) and uncommon opportunistic infections such as cryptosporidiosis, microsporidiosis, Mycobacterium avium complex (MAC) and cytomegalovirus (CMV) colitis.

Many people are unaware that they are infected with HIV.^[68] For example, less than 1% of the sexually active urban population in Africa have been tested and this proportion is even lower in rural populations.^[68] Furthermore, only 0.5% of pregnant women attending urban health facilities are counselled, tested or receive their test results.^[68] Again, this proportion is even lower in rural health facilities.^[68] Therefore, donor blood and blood products used in medicine and medical research are routinely screened for HIV.^[69] HIV-1 testing consists of initial screening with an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to HIV-1. Specimens with a nonreactive result from the initial ELISA are considered HIV-negative unless new exposure to an infected partner or partner of unknown HIV status has occurred. Specimens with a reactive ELISA result are retested in duplicate.^[70] If the result of either duplicate test is reactive, the specimen is reported as repeatedly reactive and undergoes confirmatory testing with a more specific supplemental test (e.g., Western blot or, less commonly, an immunofluorescence assay (IFA)). Only specimens that are repeatedly reactive by ELISA and positive by IFA or reactive by Western blot are considered HIV-positive and indicative of HIV infection. Specimens that are repeatedly ELISA-reactive occasionally provide an indeterminate Western blot result, which might represent either an incomplete antibody response to HIV in specimens from infected persons or nonspecific reactions in specimens from uninfected persons.^[71] Although IFA can be used to resolve an indeterminate Western blot sample, this assay is not widely used. Generally, a second specimen should be collected >1 month later and retested for persons with indeterminate Western blot results. Although much less commonly available, nucleic acid testing (e.g., viral RNA or proviral DNA amplification method) could also help resolve an initial indeterminate Western blot in certain situations.^[70] A small number of tested specimens might provide inconclusive results because of insufficient quantity of specimen for the screening or confirmatory tests. In these situations, a second specimen is collected and tested for HIV infection.

There is currently no vaccine or cure against HIV or AIDS. The only known method of prevention is based on avoiding exposure to the virus, however, an antiretroviral treatment, known as post-exposure prophylaxis is believed to reduce the risk of seroconversion if implemented directly after a highly significant exposure.^[72] Current treatment for HIV infection consists of highly active antiretroviral therapy, or HAART.^[73] This has been highly beneficial to many HIV-infected individuals since its introduction in 1996 when the protease inhibitor-based HAART initially became available.^[74] Current optimal HAART options consist of combinations (or "cocktails") consisting of at least three drugs belonging to at least two types, or "classes," of anti-retroviral agents. Typical regimens consist of two nucleoside analogue reverse transcriptase inhibitors (NARTIs or NRTIs) plus either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI). Because HIV disease progression in children is more rapid than in adults, and laboratory parameters are less predictive of risk for disease progression, particularly for young infants, treatment recommendations are more aggressive for children than for adults.^[75] In developed countries where HAART is available, doctors assess the viral load, rapidity in CD4 decline, and patient readiness while deciding when to recommend initiating treatment.^[76]

HAART allows the stabilisation of the patient’s symptoms and viremia, but it neither cures the patient of HIV, nor alleviates the symptoms, and high levels of HIV-1, often HAART resistant, return once treatment is stopped.^[77][78] Moreover, it would take more than the lifetime of an individual to be cleared of HIV infection using HAART.^[79] Despite this, many HIV-infected individuals have experienced remarkable improvements in their general health and quality of life, which has led to the plummeting of HIV-associated morbidity and mortality.^[74][80][81] In the absence of HAART, progression from HIV infection to AIDS occurs at a median of between nine to ten years and the median survival time after developing AIDS is only 9.2 months.^[82] Still, for some patients - and in many clinical cohorts this may be more than fifty percent of patients - HAART achieves far less than optimal results. This is due to a variety of reasons such as medication intolerance/side effects, prior ineffective antiretroviral therapy and infection with a drug-resistant strain of HIV. However, non-adherence and non-persistence with antiretroviral therapy is the major reason most individuals fail to get any benefit from and develop resistance to HAART.^[83] The reasons for non-adherence and non-persistence with HAART are varied and overlapping. Major psychosocial issues, such as poor access to medical care, inadequate social supports, psychiatric disease and drug abuse contribute to non-adherence. The complexity of these HAART regimens, whether due to pill number, dosing frequency, meal restrictions or other issues along with side effects that create intentional non-adherence also has a weighty impact.^[84][85][86] The side effects include lipodystrophy, dyslipidaemia, insulin resistance, an increase in cardiovascular risks and birth defects.^[87][88]

Anti-retroviral drugs are expensive, and the majority of the world's infected individuals do not have access to medications and treatments for HIV and AIDS.^[89] Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug regimens to improve adherence, and determining the best sequence of regimens to manage drug resistance. Only a vaccine is postulated to be able to halt the pandemic. This is because a vaccine would possibly cost less, thus being affordable for developing countries, and would not require daily treatments.^[89] However, after over 20 years of research, HIV-1 remains a difficult target for a vaccine.^[89]

UNAIDS and the WHO estimate that AIDS has killed more than 25 million people since it was first recognized in 1981, making it one of the most destructive epidemics in recorded history. Despite recent, improved access to antiretroviral treatment and care in many regions of the world, the AIDS epidemic claimed an estimated 2.8 million (between 2.4 and 3.3 million) lives in 2005 of which more than half a million (570,000) were children.^[3]

Globally, between 33.4 and 46 million people currently live with HIV.^[3] In 2005, between 3.4 and 6.2 million people were newly infected and between 2.4 and 3.3 million people with AIDS died, an increase from 2004 and the highest number since 1981.

Sub-Saharan Africa remains by far the worst-affected region, with an estimated 21.6 to 27.4 million people currently living with HIV. Two million [1.5–3.0 million] of them are children younger than 15 years of age. More than 64% of all people living with HIV are in sub-Saharan Africa, as are more than three quarters (76%) of all women living with HIV. In 2005, there were 12.0 million [10.6–13.6 million] AIDS orphans living in sub-Saharan Africa 2005.^[3] South & South East Asia are second worst affected with 15%. AIDS accounts for the deaths of 500,000 children in this region. Two-thirds of HIV/AIDS infections in Asia occur in India, with an estimated 5.7 million infections (estimated 3.4—9.4 million) (0.9% of population), surpassing South Africa's estimated 5.5 million (4.9-6.1 million) (11.9% of population) infections, making it the country with the highest number of HIV infections in the world.^[90] In the 35 African nations with the highest prevalence, average life expectancy is 48.3 years—6.5 years less than it would be without the disease.^[91]

The latest evaluation report of the World Bank's Operations Evaluation Department assesses the development effectiveness of the World Bank's country-level HIV/AIDS assistance defined as policy dialogue, analytic work, and lending with the explicit objective of reducing the scope or impact of the AIDS epidemic.^[92] This is the first comprehensive evaluation of the World Bank's HIV/AIDS support to countries, from the beginning of the epidemic through mid-2004. Because the Bank's assistance is for implementation of government programmes by government, it provides important insights on how national AIDS programmes can be made more effective.

The development of HAART as effective therapy for HIV infection and AIDS has substantially reduced the death rate from this disease in those areas where it is widely available. This has created the misperception that the disease has gone away. In fact, as the life expectancy of persons with AIDS has increased in countries where HAART is widely used, the number of persons living with AIDS has increased substantially. In the United States, the number of persons with AIDS increased from about 35,000 in 1988 to over 220,000 in 1996.^[93]

In Africa, the number of MTCT and the prevalence of AIDS is beginning to reverse decades of steady progress in child survival. Countries such as Uganda are attempting to curb the MTCT epidemic by offering VCT (voluntary counselling and testing), PMTCT (prevention of mother-to-child transmission) and ANC (ante-natal care) services, which include the distribution of antiretroviral therapy.