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The human immunodeficiency virus (HIV) is a frequently mutating retrovirus that attacks the human immune system and which has been shown to cause acquired immune deficiency syndrome (AIDS).
HistoryThe first AIDS cases were described in 1981. HIV was discovered and identified as the agent for AIDS by Luc Montagnier of France and Robert Gallo of the United States in 1983-1984, leading to some controversy regarding the priority. At the time, the virus was called Human T-Lymphotropic Virus type III (HTLV-III) or Lymphadenopathy-Associated Virus (LAV). In 1986, the genome of the virus was cloned and sequenced. The name HIV has been in use since 1986. As of the end of 2004, there were an estimated 39.4 million people around the world living with HIV or AIDS, 25.4 million of whom were in sub-Saharan Africa. In some parts of the United States, it is illegal for a person with HIV to knowingly infect a person with the virus. This is also the case in most Western countries. Signs and symptomsAcute infection with HIV is a very aspecific syndrome, which is easily missed due to its likeness to infectious mononucleosis and other viral infections. Fever, fatigue and rash are the most common symptoms, and many develop lymphadenopathy (swollen lymph nodes). Pharyngitis, myalgia and several other symptoms also occur (Kahn & Walker, 1998). This seroconversion syndrome is different from AIDS, the immune disease that most untreated HIV-infected patients develop eventually. A very small minority of scientists continue to question the connection between HIV and AIDS and even the very existence of HIV (see AIDS reappraisal). Shortly after infection, the body produces specific antibodies; most HIV tests work by detecting the presence of these antibodies. The virusHIV has several major genes coding for structural proteins that are found in all retroviruses, and several non-structural or "accessory" genes that are unique to HIV.
Types of HIV and their originsSince 1986, it has been recognized that there are two species of the virus: HIV-1 and HIV-2. They differ in their genome and in their infectivity, with HIV-1 being well over three times as infective as HIV-2 (Gilbert 2002). Furthermore, it takes longer for HIV-2 infection to cause disease. HIV-2 infections are mostly found in Western Africa and, increasingly, in India; HIV-1 is endemic in the rest of the world. Both HIV types are closely related to Simian Immunodeficiency Virus (SIV), with HIV-1 more closely related to the chimpanzee strain of SIV than to HIV-2, and HIV-2 more closely related to the Sooty Mangabey strain of SIV than to HIV-1. It is likely that HIV was introduced into humans in Africa via contact with the blood of hunted monkeys, in the first half of the 20th century (Sharp 2001). HIV-1 is further subdivided into three groups: M, O and N. The groups N and O appear to be confined to Africa, with N being very rare. The three groups probably resulted from three different human/monkey contacts. The major group, M, is further divided into numerous subgroups or clades, identified by letters. HIV and the immune responseMissing image Hiv-timecourse.png Graph showing HIV virus and CD4+ levels over the course of an untreated infection Infection begins with an acute viremia. After this acute phase, the virus count drops up to 100 fold. From this alone, we see that the body seems to have a response to the HIV virus. After the acute viremia, a period of clinical latency begins. At first this was believed to be true viral latency whereby the HIV was inserted in the host genome in an unproductive state awaiting certain body conditions to begin transcription. This implied the final fatal phase was just a breakdown of the asymptomatic phase causing transcription. There was subsequently a great deal of research into HIV transcription factors. Unfortunately, until about 1993, the sensitivity of viral assays was very poor meaning useful advances were not possible. The use of PCR amplification techniques from 1993 onwards meant that viral counts as low as 50 copies/ml were now detectable. Around this time, attention also switched to the analysis of HIV in lymphoid tissue. Dendritic cells were found coated with virions, showing that the so called latent phase is not latent at all, virus levels are still high. Steady-state hypothesisMissing image Hiv-monotherapy-levels.png Sketch graph showing speed of mutant HIV recovery after administration of protease inhibitor monotherapy The next clues to the nature of this period of clinical latency came with the first use of antiretroviral protease inhibitor monotherapy [1] (http://www.nature.com/cgi-taf/DynaPage.taf?file=/nature/journal/v373/n6510/abs/373123a0.html&dynoptions=doi1099935896). From the period of clinical latency (a steady state), the viral titre quickly dropped to almost undetectable levels. Also the CD4+ levels quickly increased. Within seven to fourteen days however, levels of mutant virus resistant to the protease inhibitor increased dramatically and the CD4 levels returned to their previous levels at clinical latency. Assuming that the protease inhibitor was 100% effective, the rate of fall of HIV levels equals the rate of HIV production during the steady state or clinical latency period. The rate of HIV production during this period was found to be 108 - 109 virions per day, 30% of the total virus. Similarly the CD4+ cell turnover was found to be 2x109 cells per day. This implies a constant dynamic struggle between the virus and the host, and raises the possibility that the end of the period of clinical latency is due to the host becoming drained and not able to produce any more CD4+ cells. The rapid drug resistant variant problem was particularly disheartening for researchers at the time. Although HIV has a high copy error rate (making the creation of drug resistant mutants more likely) it is not significantly higher than other known viruses which do not create mutants as rapidly. HIV is able to so quickly create drug resistant mutants due to its high error rate combined with its enormous virion turnover rate. This highlights the importance of antiretroviral combination therapy over standard monotherapy. CD4+ cell depletion controversyAfter further research, part of the rise in the CD4+ cell levels in the above graph appeared to be due to a redistribution of lymphoid tissue and blood. A study by Hellerstein [2] (http://www.nature.com/cgi-taf/DynaPage.taf?file=/nm/journal/v5/n1/full/nm0199_83.html) used deutero glucose pulse labelling to show that CD4+ cell survival rate in HIV infected hosts decreased by a third, but there was no effect on the rate of production. This implied that CD4+ loss during HIV infection is due to both a shortened survival time of CD4+ cells and a failure to increase levels of CD4+ production. Another review by Douek [3] (http://arjournals.annualreviews.org/doi/full/10.1146/annurev.immunol.21.120601.141053;jsessionid=iPdXeA4yjvja) looked at the level of thymic re-arrangement excision circles (TRECs) in HIV infected hosts. TRECs are markers for recent thymic emigrants, and their level was found to be substantially reduced in HIV infected hosts. This, along with the recovery of thymic function upon HAART treatment implies that HIV markedly impairs thymic function. Pathogenesis HIV causes disease by infecting the CD4+ T cells. These are a subset of leukocytes (white blood cells) that normally coordinate the immune response to infection. By using CD4+ T cells to replicate itself, HIV spreads throughout the body and at the same time depletes the very cells that the body needs to fight the virus. Once an HIV-positive individual's CD4+ T cell count has decreased to a certain threshold, they are prone to a range of diseases that the body can normally control. These opportunistic infections are usually the cause of death. There are several reasons why HIV is so hard to fight. First, the virus is an RNA virus, using the reverse transcriptase enzyme to convert its RNA into DNA. This additional process results in a greater chance of mutation than in DNA viruses. Therefore, the virus becomes quickly resistant to therapy. Second, the common notion that HIV is a killer feasting on T cells is not true. If HIV were a killer virus, it would have died out soon because there would be too little time for new infections. In reality, HIV stays in the body for years, infecting people through unsafe sex, blood transfusions and breastfeeding of infants by mothers oblivious to their infection. HIV can survive even when drugs eliminate all detectable virons in the blood (viremia). It integrates itself into the DNA of the host cell and can stay there for years, lying dormant, immune to all kinds of therapy because it is just DNA. When the cell divides and the DNA is copied, the virus is copied too. After years, the virus can become active again, seize the cell's machinery and replicate. In recent years, the notion that the CD4+ T cells decrease because of direct HIV infection has become doubted as well. The HIV coating protein readily detaches from virus particles. The blood becomes filled with these proteins, which can stick to the CD4+ T cells, gluing them together. In addition, they are recognized by the immune system, causing the immune cells to attack their own CD4+ cells. Treatment The chemical structure of AZT. AZT, a reverse transcriptase inhibitor, was the first treament for HIV Patients today are given a complex regimen of drugs that attack HIV at various stages in its life cycle. These are known as antiretroviral drugs. They include:
Many problems are involved in establishing a course of treatment for HIV. Each effective drug comes with side effects, often serious and sometimes life-threatening in themselves. Common side effects include extreme nausea and diarrhea, liver damage and failure, and jaundice. Any treatment requires regular blood tests to determine continued efficacy (in terms of T-cell count and viral load) and liver function. Also, no cases are known in which antiviral therapy has been able to terminate HIV infection. More than incremental improvements will be required to change this picture, meaning that HIV-infected people will likely have to stay on treatment life-long. Still, mortality is much lower among people with properly treated HIV infection than among HIV-positive people who got treated either at a late stage of infection or not at all. An important consequence of this is that people with access to adequate healthcare who have acquired HIV are today much better off if they know their status than if they learn about their infection only when symptoms of immune decline appear. ImmunityAbout 10% of all Europeans carry a polymorphism of CCR5, a cell surface receptor involved in M-tropic HIV-1 infections. M-tropic HIV-1 uses CCR5 and CD4 receptors to enter target cells, unlike T-tropic HIV which uses CXCR4 with CD4. About 1% of all Europeans are homozygous for this mutation (a 32 base pair deletion), and have a very low risk of HIV-1 infection, although not complete protection. Common misconceptions regarding HIV
Life cycle of HIVHIV enters a CD4+ helper T-cell by bonding with either CXCR4 or both CXCR4 and CCR5 depending on what stage the HIV infection is in. A cofactor protein (fusin) is required to assist binding of the viron to the membrane of the T-cell. During the early phases of an HIV infection typically both CCR5 and CXCR4 are bound while late stage infection often involve HIV mutations that only bind to CXCR4. Once HIV has bound to the CD4+ T-cell a viral protein known as GP41 penetrates the cell membrane and the HIV RNA and various enzymes including but not limited to reverse transcriptase, integrase and protease are injected into the cell. The host T-cell can process RNA into proteins (as in Polio virus) but this doesn't happen with HIV. Instead, HIV is stabilised by copying it into DNA and inserting it into the host cell's chromosomes. This means the virus can perform more subtle functions by using the host transcription machinery. The virus generates DNA from the HIV RNA using the reverse transcriptase enzyme to perform reverse transcription. This process can be inhibited by drugs. If this succeeds the pro-viral DNA must then be integrated into the host cell DNA using the integrase enzyme. If the pro-viral DNA becomes integrated into the host cell's DNA the cell is now fully infected but not actively producing HIV proteins. This is the latent stage of HIV an infection during which the infected cell can be an "unexploded bomb" for potentially a long time. 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 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! 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). The virus starts to form under the cell membrane, in special cholesterol-rich regions, and gradually buds outside. Once outside it has to undergo a maturation step or else it isn't infectious. The virus protease enzyme cleaves Gag into several smaller proteins (Matrix, Capsid, p2, Nucleocapsid, p1 and P6) and this step can be inhibited by drugs. The virus is then able to infect a further cell. Structure of the virusHIV looks quite different to the classic retroviruses described in the 1960's. It is around 120nm in diameter (120 billionths of a meter - a red blood cell is around 60 times larger at 7 millionths of a meter) and roughly spherical. There are two forms of the virus. They both consist of a lipid envelope surrounding a protein/RNA core. Immature form. When the virus leaves the cell it is not infectious and the inner part of the virus particle contains a spherical core (stains dark on electron micrographs). There are also spikes on the outer membrane that are the Env proteins (gp120 and gp41). Sometimes a virus can be seen during the process of budding, when it looks like a dark arc sitting under the cell membrane - this observation meant that HIV was originally classed as a type C retrovirus. The Env proteins link together in groups of three (trimers). Mature form. Once the virus protease has cleaved the Gag proteins, the core rearranges into a truncated cone (imagine a traffic cone sliced at an angle across the top!) Some reports also show a small filament linking the core to the membrane. The envelope spikes are often much rarer on mature particles since they are easily dislodged. It is the mature conical core that makes HIV so easily identifiable. Inside the virus there are two identical strands of RNA, in the same way that we have two identical copies of each chromosome. The RNA is coated by the CA protein (formed from Gag) and is not easily seen unless the virus particles are broken apart. The reverse transcriptase enzyme, which includes integrase, is also packaged into the virus along with certain other important proteins (some from the virus, some captured from the cell) and a tRNA molecule that initiates the reverse transcription process. Because the virus contains certain proteins it needs to replicate, injection of the pure RNA will not result in a successful infection.
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de:HIV eo:HIV es:VIH fr:Virus de l'immunodéficience humaine it:HIV ja:ヒト免疫不全ウイルス nl:HIV no:HIV pl:Wirus nabytego niedoboru odporności pt:HIV ru:ВИЧ sv:HIV zh:人体免疫缺陷病毒 |
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