HIV

? Human immunodeficiency virus
Stylized rendering of a cross section of the human immunodeficiency virus
Virus classification
Group: Group VI ( ssRNA-RT) Family: Retroviridae Genus: Lentivirus Species: Human immunodeficiency virus 1 Species: Human immunodeficiency virus 2

International Statistical Classification of Diseases and Related Health Problems Codes

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ICD-10	B20-B24
ICD-O:	{{{ICDO}}}
ICD-9	042-044
DSM-IV	{{{DSM-IV}}}
OMIM	{{{OMIM}}}
MedlinePlus	{{{MedlinePlus}}}
eMedicine	{{{eMedicineSubj}}}/{{{eMedicineTopic}}}
DiseasesDB	{{{DiseasesDB}}}

Human immunodeficiency virus, commonly known by the initialism HIV, formally known as HTLV-III and lymphadenopathy-associated virus, is a retrovirus that primarily infects vital components of the human immune system such as CD4+ T cells, macrophages and dendritic cells. It also directly and indirectly destroys CD4+ T cells. As CD4+ T cells are required for the proper functioning of the immune system, when enough CD4+ T cells have been destroyed by HIV, the immune system functions poorly, leading to the syndrome known as AIDS. HIV also directly attacks organs, such as the kidneys, the heart and the 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.

HIV is transmitted through direct contact of a mucous membrane with a bodily fluid containing HIV, such as blood, semen, vaginal fluid, preseminal fluid or breast milk. This transmission can come in the form of: penetrative ( anal or vaginal) sex; oral sex; blood transfusion; contaminated needles; exchange between mother and infant during pregnancy, childbirth, or breastfeeding; or other exposure to one of the above bodily fluids.

AIDS is thought to have originated in sub-Saharan Africa during the twentieth century and it is now a pandemic. At the end of 2004, UNAIDS estimated that nearly 40 million people were currently living with HIV . The World Health Organization estimated that the AIDS epidemic had claimed more than 3 million people and that 5 million people had acquired HIV in the same year. Currently it is estimated that 28 million people have died and that it is set to infect 90 million people in Africa, resulting in a minimum estimate of 18 million orphans in Africa alone .

Introduction

In 1983, scientists led by Luc Montagnier at the Pasteur Institute in France first discovered the virus that causes AIDS . 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) . The dual discovery led to considerable scientific fall-out, and it was not until President Mitterand of France and President Reagan of the USA met that the major issues were ironed out. In 1986, both the French and the US names were dropped in favour of the new term human immunodeficiency virus (HIV) .

HIV is a member of the genus lentivirus , part of the family of retroviridae. 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 . 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 for replication using cellular machinery. 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, 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 the more virulent and easily transmitted, and is the source of the majority of HIV infections throughout the world; HIV-2 is largely confined to west Africa . Both species originated in west and central Africa, jumping from primates to humans in a process known as zoonosis. HIV-1 has evolved from a simian immunodeficiency virus (SIVcpz) found in the chimpanzee subspecies, Pan troglodytes troglodytes . HIV-2 crossed species from a different strain of SIV, found in sooty mangabey monkeys in Guinea-Bissau . It is possible that that HIV-1 entered the human populations in the 1930's.

Another controversial possibility for the origin of HIV/AIDS was discussed in a 1992 Rolling Stone magazine article by freelance journalist Tom Curtis. He put forward the theory that AIDS was inadvertantly caused in the late 1950's in the Belgian Congo by Hilary Koprowski's research into a polio vaccine . Although subsequently retracted due to libel issues surrounding its claims, the Rolling Stone article encouraged another freelance journalist, Edward Hooper, to travel to Africa for 7 years of research 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 SIV mutated into HIV and started the human AIDS epidemic, some time between 1957 to 1959 .

Transmission

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 mouth mucous membranes of another. According to the French ministry for health, the probability of transmission per act varies from 0.03% to 0.07% for the case of receptive vaginal sex, from 0.02 to 0.05% in the case of penetrative vaginal sex, from 0.01% to 0.185% in the case of penetrative anal sex, and 0.5% to 3% in the case of receptive anal sex .

• Blood or blood product route. This transmission route is particularly important for intravenous drug users, hemophiliacs and recipients of blood transfusions 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 (e.g. reused needles in Third World settings). Health care workers (nurses, laboratory workers, doctors, etc) are also directly concerned, although more rarely. Also concerned by this route are people who give and receive tattoos, piercings and scarification procedures.

• Mother-to-child route. The transmission of the virus from the mother to the child can occur in utero during the last weeks of pregnancy and at childbirth. Breast feeding also presents a risk of infection for the baby. In the absence of treatment, the transmission rate between the mother and child was 20%. However, where treatment is available, combined with the availability of Cesarian section, this has been reduced to 1%.

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 considered to be negligible.

The use of physical barriers such as the latex condom is widely advocated to reduce the sexual transmission of HIV. Recently, it has been proposed that male circumcision may reduce the risk of HIV transmission , but many experts believe that it is premature to recommend male circumcision as part of HIV prevention programs .

The clinical course of HIV-1 infection

Infection with HIV-1 is associated with a progressive loss of CD4+ T-cells. This rate of loss can be measured and is used to determine the stage of infection. The loss of CD4+ T-cells is linked with an increase in viral load. The clinical course of HIV-infection generally includes three stages: primary infection, clinical latency and AIDS (Figure 1). HIV plasma levels during all stages of infection range from just 50 to 11 million virions per ml .

Primary Infection

Primary, or acute infection is a period of rapid viral replication that immediately follows the individual's exposure to HIV. During primary HIV infection, 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 . 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. Since not all patients develop it, and since the same symptoms can be caused by many other common diseases, it cannot be used as an indicator of HIV infection. However, recognizing the syndrome is important because the patient is much more infectious during this period.

Clinical Latency

A strong immune defense reduces the number of viral particles in the blood stream, marking the start of the infection's clinical latency stage (Figure 1). 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. The surrounding tissues that are rich in CD4+ T-cells 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 declaration of AIDS

AIDS is the most severe manifestation of infection with HIV. Acute HIV infection progresses over time to clinical latent HIV infection and then to early symptomatic HIV infection and later, to AIDS, which is identified on the basis of certain infections.

HIV structure and genome

HIV is different in structure from previously described retroviruses. It is around 120 nm in diameter (120 billionths of a meter; around 60 times smaller than a red blood cell) and roughly spherical.

HIV-1 is composed of two copies of single-stranded RNA enclosed by a conical capsid, which is in turn surrounded by a plasma membrane that is formed from part of the host-cell membrane. Other enzymes contained within the virion particle include reverse transcriptase, integrase, and protease.

HIV has several major genes coding for structural proteins that are found in all retroviruses, and several nonstructural ("accessory") genes that are unique to HIV. The gag gene provides the physical infrastructure of the virus; pol provides the basic enzymes by which retroviruses reproduce; the env gene supplies the proteins essential for viral attachment and entry into a target cell. The accessory proteins tat, rev, nef, vif, vpr, and vpu enhance virus production. Although called accessory proteins, tat and rev are essential for virus replication. In some strains of HIV, a mutation causes the production of an alternate accessory protein, Tev, from the fusion of tat, rev, and env.

The gp120 and gp41 proteins, both encoded by the env gene, enable the virus to attach to and fuse with target cells to initiate the infectious cycle. Both, especially gp120, have been considered as targets of future treatments or vaccines against HIV.

HIV tropism

The term viral tropism refers to the cell type that the virus infects and replicates in. HIV can infect a variety of cells such as CD4+ helper T-cells and macrophages that express the CD4 molecule on its surface. HIV-1 entry to macrophages and T helper 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. Macrophage (M-tropic) strains of HIV-1, or non-syncitia-inducing strains (NSI) use the beta- chemokine receptor CCR5 for entry and are thus able to replicate in macrophages and CD4+ T-cells . 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 alpha-chemokine receptor, CXCR4, for entry . The alpha-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. Viruses 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 .

HIV can also infect a subtype of dendritic cells , MDC-1, which probably constitute a major reservoir that maintains infection when T helper cell numbers have declined to extremely low levels.

Replication cycle of HIV

Figure 2. The HIV replication cycle

Figure 3. The immature and mature forms of HIV

Viral entry to the cell

The interaction between the glycoprotein gp120 on the HIV virion and its receptor, CD4 on the target cell, provokes conformational changes in gp120. This exposes a region of gp120, the V3 loop, which binds to a cytokine receptor on the target cell, such as CCR5 or CXCR4 depending on the strain of HIV. Without a coreceptor, fusion does not take place, explaining why HIV favors some types of CD4+ cells over others.

The change in gp120's shape also exposes a portion of the gp41 glycoprotein, which was previously buried in the viral membrane and loosely bound to gp120. A fusion peptide within gp41 causes the fusion of the viral envelope and the host-cell envelope, allowing the capsid to enter the target cell. The exact mechanism by which gp41 causes the fusion is still largely unknown .

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.

Viral replication and transcription

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) (Figure 2). 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. This is called the latent stage of HIV infection . To actively produce virus, certain transcription factors need to be present in the cell. The most important is called NF-kB (NF Kappa B) and is present once the T cells becomes activated. This means that those cells most likely to be killed by HIV are in fact those currently fighting infection.

The production of the virus is regulated, like that of many viruses. 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 . 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.

Interestingly, 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 causes AIDS faster than HIV-2 and is the majority species of the virus).

Viral assembly and release

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 . This step can be inhibited by drugs. The virus is then able to infect another cell.

Genetic variability of HIV

Figure 4. The phylogenetic tree of the SIV and HIV viruses (click on image for a detailed description).

Figure 5. Map showing HIV-1 subtype prevalence. The bigger the pie chart, the more infections are present.

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. 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. This recombination is most obvious when it occurs between subtypes.

Three groups of HIV-1 have been identified on the basis of differences in env: M, N and O (Figure 4). Group M is the most prevalent and is subdivided into eight subtypes, based on the whole genome, that are each geographically distinct . 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) (Figure 5); these subtypes form branches in the phylogenetic tree representing the lineage of the M group of HIV-1 (Figure 4). 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 (Figure 5). Almost 95% of all HIV research currently taking place is focused on subtype B, while a few laboratories focus on other subtypes.

Treatment

HIV infection is a chronic infectious disease that can be treated, but not yet cured. There are effective means of preventing complications and delaying progression to AIDS. At the present time, not all persons infected with HIV have progressed to AIDS, but it is generally believed that the majority will. People with HIV infection need to receive education about the disease and treatment so that they can be active partners in decision making with their health care provider.

A combination of several antiretroviral agents, termed Highly Active Anti-Retroviral Therapy HAART, has been highly effective in reducing the number of HIV particles in the blood stream (as measured by a blood test called the viral load). This can improve T-cell counts. This is not a cure for HIV, and people on HAART with suppressed levels of HIV can still transmit the virus to others through sex or sharing of needles. There is good evidence that if the levels of HIV remain suppressed and the CD4 count remains greater than 200, then the quality and length of life can be significantly improved and prolonged. Improved antiretroviral inhibitors against proteins such as Reverse transcriptase, Integrase and Tat are being researched and developed. One of the most promising new therapies is a new class of drugs called fusion or entry inhibitors.

For more details on this topic, see Antiretroviral drug.

Post-exposure prophylaxis (PEP) with a course of antiviral drugs is also thought to reduce the risk of seroconversion after high risk exposure (unprotected anal or vaginal sex) to HIV . To be effective, it must be started as soon as possible after exposure and no later than 72 hours post-exposure. The treatment for HIV lasts four weeks. While there is compelling data to suggest that PEP after HIV exposure is extremely effective, there have been cases where it has failed.

As yet, no vaccine has been developed to prevent HIV infection or disease in people who are not yet infected with HIV, but the potential worldwide public health benefits of such a preventive vaccine are vast. Researchers in many countries are seeking to produce such a vaccine, including through the International AIDS Vaccine Initiative.

Epidemiology

Figure 6. The adult HIV prevalence at the end of 2004

UNAIDS and the WHO estimated that between 37 and 45 million people around the world were living with HIV in December 2005 . It was estimated that during 2005, between 4.9 and 6.6 million people were newly infected with HIV and between 2.8 and 3.6 million people with AIDS died . Sub-Saharan Africa remains by far the worst-affected region, with 23.8 million to 28.9 million people living with HIV at the end of 2005. The proportion of women being affected by the epidemic continues, in 2005, 16.2–19.3 million women were living with HIV — one million more than in 2003. Just under two thirds (64%) of all people living with HIV are in sub-Saharan Africa, as are more than three quarters (77%) of all women living with HIV . South & South East Asia are second most affected with 18%. AIDS accounts for the deaths of 500,000 children.

The epidemic is not homogeneous within regions with some countries more afflicted than others (Figure 6). Even at the country level there are wide variations in infection levels between different areas, sexes and socioeconomic situation. The number of people living with HIV continues to rise in but in several countries it declines. Evidence points out that changes in sexual behaviour, such as increased use of condoms, fewer sexual partners and delay of sexual experience, played key parts in these declines. The steepest increases have occurred in in Eastern Europe and Central Asia (25% increase to 1.6 million) and East Asia .