- |Human immunodeficiency virus (commonly known as HIV, and formerly known as HTLV-III and lymphadenopathy-associated virus) 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.
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.|format=
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.|format= 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).|format= The dual discovery led to considerable scientific fallout, and it was not until President Mitterrand 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 for the virus itself were dropped in favour of the new term, human immunodeficiency virus (HIV).|format=
HIV was classified as a member of the genus lentivirus,|format= 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. |format=|format= HIV-2 is hypothesized to have originated from the Sooty Mangabey (Cercocebus atys), an Old World monkey of Guinea-Bissau, Gabon, and Cameroon. 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. 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:#A plasma sample taken in 1959 from an adult male living in what is now the Democratic Republic of Congo.#HIV found in tissue samples from a 15 year old African-American teenager who died in St. Louis in 1969.
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 poliovaccine.
Exposure Route
Estimated infections per 10,000 exposures to an infected source
Blood Transfusion
9,000
Childbirth
2,500|format=}}
Needle-sharing injection drug use-
67
Receptive anal intercourse*
50|format=}}|format=}}
Percutaneous needle stick
30
Receptive penile-vaginal intercourse*
10
Insertive anal intercourse*
6.5
Insertive penile-vaginal intercourse*
5
Receptive fellatio*
1
Insertive fellatio*
0.5
* assuming no condom use
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 is particularly important for 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 (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 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%. However, where treatment is available, combined with the availability of Cesarian section, this has been reduced to 1%. 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 latexcondom 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.
UNAIDS believes that it is premature to recommend male circumcision services as part of HIV prevention programs 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.
Diagram of HIV
HIV is different in structure from previously described 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.
It is composed of two copies of positive single-stranded RNA enclosed by a conical capsid, which is in turn surrounded by a plasma membrane that is formed from part of the former 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 it. 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 transactivators 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 form gp160 before cleavage to two separate proteins, 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.
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.
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.|format= 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.
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 and HIV can also infect a subtype of myeloid dendritic cells,
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. An example of this is people with the CCR5-Î"32 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.
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
and that genital epithelial cells preferentially sequester X4 virus.
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.
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.
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.
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.
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. 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. 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. This allows for a more stable two-pronged attachment, which leads to the N-terminal fusion peptide gp41 to penetrate the cell membrane. 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.
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HIV infects dendritic cells (DCs) by intimate contact of naive CD4+ T cells during the course of antigen presentation by a gp120/gp41 independent route using mannose-specific C-type lectin receptors such as DC-SIGN.
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.
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). 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 cellular transcription factors need to be present, the most important of which is (NF kappa B), which is upregulated when the T cell becomes activated. 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 mRNAsplicing.
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).
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.
The phylogenetic tree of the SIV and HIV (click on image for a detailed description).
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.
Group M is the most prevalent and is subdivided into eight subtypes (or clades), 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); 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.
Almost 95% of all HIV research currently taking place is focused on subtype B, while a few laboratories focus on other subtypes.
Infection with HIV-1 is associated with a progressive loss of CD4+ T cells (lymphocytes). 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. HIV plasma levels during all stages of infection range from just 50 to 11 million virions per mL.
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 infection
[[Image:Hiv-timecourse.png|400px|thumb|right|A generalized graph of the relationship between HIV copies (viral load) and CD4 counts over the average course of untreated HIV infection; any particular individual's disease course may vary considerably.
]]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. The CD4+ T cell count is still higher than 1000 cells per µL.
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. 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 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, the most prevalent cell infected is the macrophage.
Symptoms of early infection
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.
Approximately half of those infected do not know their HIV status until it has progressed to an AIDS diagnosis. At this point many people tend to show opportunistic infection, who then see a doctor, get an HIV test and discover they are HIV positive. Donor blood and blood products used in medicine and medical research are screened for HIV using such a test. Typical HIV tests, including the HIV enzyme immunoassay and the Western blot assay, detect HIV antibodies in serum, plasma, oral fluid, dried blood spot or urine of patients. However, the time between initial infection and the development of detectable antibodies against HIV can vary. This is called the window period. This is why it can take 6-12 months to seroconvert and test positive. There are tests to detect other HIV antigens, HIV-RNA, and HIV-DNA in order to detect HIV infection prior to the development of detectable antibodies. HIV tests to detect antibodies, antigens or ribonucleic acid (RNA) in serum, plasma, oral fluid, dried blood spot or urine have been approved by FDA for donor screening, diagnosis, prognosis and patient monitoring.
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.
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.
Current drug classes include NNRTI, NRTI, NtRTI, PI, FI. Each of the drugs in these classes represent individual pharmacodynamics and toxicities, requiring expert knowledge to appropriately select and dose an effective combination. Current recommendations for treatment include at least a three drug effective regime to induce complete cease of viral replication and reduce the incidence of new mutations. On July 12, 2006 Atripla, a combination of the three widely used anti-retroviral drugs was fast-tracked by the FDA and will be made available for purchase in 15 other countries under a US international AIDS relief programme. 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.
[[Image:HIV Epidem.png|290px|thumb|right|Prevalence of HIV among adults per country at the end of 2005
]]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.
Globally, between 33.4 and 46 million people currently live with HIV. 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 [1.5â€"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 [10.6â€"13.6 million] AIDS orphans living in sub-Saharan Africa 2005.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.Some scientists and activist groups question the connection between HIV and AIDS, the alleged danger of HIV, or the validity of current testing methods. These claims are met with resistance by, and often evoke frustration and hostility from, members of both the medical community, and the scientific community. These proponents for re-evaluation for HIV as the cause of AIDS bring forth such points as Koch's postulates, suggesting that since HIV is not present in 100% of AIDS cases, HIV can not be the sole cause of AIDS. HIV also does not always lead to AIDS when injected into a new, healthy host and be found to be growing again in this host. | format=
url=http://www.sciencemag.org/feature/data/cohen/266-5191-1642a.pdf}} Dissidents assert that the current mainstream approach to AIDS, based on HIV causation, has resulted in inaccurate diagnoses, psychological terror, toxic treatments, and a squandering of public funds. The debate and controversy regarding this issue from the early 1980s to the present has provoked heated emotions and passions from both sides.
