HIV

History

HIV was discovered and identified as the agent for AIDS by Luc Montagnier of France and Robert Gallo of the United States.

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).

As of 27 November 2003, there were an estimated 54,862,417 worldwide HIV infections, 30% of which were in Southern Africa.

For a person with HIV in the United States to knowingly infect a person with the virus is a crime in every state of the union.

Signs and symptoms

This section deals with seroconversion syndrome. This is not identical to AIDS.

Acute 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).

The virus

HIV has several major genes coding for structural proteins.

• General retrovirus genes
  • gag. gag derived proteins make up the cone-shaped viral capsid (p24, i.e. a 24 Kilodalton protein, CA) the nucleocapsid protein (p17, NC) and a matrix protein (MA).
  • pol. The pol gene codes for the virus enzymatically active proteins. Most important is the so-called reverse transcriptase (RT) which performs the unique reverse transcription of the viral RNA into double-stranded DNA. The latter is integrated into the genome of the host, which means into a chromosome of an infected cell of an HIV-positive person by the pol-encode integrase (IN). Also, pol encodes a specific viral protease(PR). This enzyme cleaves gag- and gag-pol-derived proteins into functional pieces.
  • env. env, stands for "envelope". The proteins derived from env are a surface (gp120) and a transmembrane protein (gp41). They are located at the outer part of the virus particle and enable the virus to attach to and to fuse with the target cells to initiate the infectious cycle. gp has a knoblike structure.
• Specific HIV genes
  • tat A portion of the HIV RNA structure is a hairpin structure which initially prevents full transcription taking place. Part of the RNA that is transcribed (ie. before the hairpin portion) encodes the tat protein. tat binds to CdK9/CycT and phosphorylates it, helping to alter it's shape and eliminating the effect of the hairpin RNA structure. This itelf increases the rate of trancription, providing a positive feedback cycle. This allows HIV to have an explosive response once a threshold amount of tat is produced, a useful tool in defeating the body's response.
  • rev rev allows fragments of HIV mRNA that contain a rev Response Unit (RRE) to be exported from the nucleus to the cytoplasm. In the absence of rev, RNA splicing machinery in the nucleus quickly splices the RNA making it useless. In the presence of rev, RNA is exported from the nucleus before it can be spliced. Again, this mechanism allows a positive feedback loop and allows HIV to overwhelm the host's defences.

HIV and the Immune Response

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 weren't 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 to HIV in lymphoid tissue. Dendritic cells were found coated with virions, showing that the so called latent phase isn't latent at all, virus levels are still high.

Steady state Hypothesis

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 prodcution 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 don't create mutants as rapidly. HIV is able to so quickly create drug resistant mutants due to it's high error rate combined with it's enormous virion turnover rate. This highlights the importance of antiretroviral combination therapy over standard monotherapy.

CD4⁺ Cell Depletion Controversy

After 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 replication

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. Metaphorically, HIV is guerrilla terrorist of the viral world, keeping low and seeking shelter when threatened, but always ready to hit where it hurts.

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:

• Protease inhibitors (PIs) inhibit activity of protease, an enzyme used directly by HIV to cleave nascent viral proteins, and so prevent final assembly of HIV virions.
• Reverse transcriptase inhibitors (RTIs) inhibit the activity of reverse transcriptase, an enzyme HIV needs to complete infection of a cell. Lack of this enzyme prevents HIV from building pro-viral DNA based on its RNA. They come in three forms:
  • Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
  • Nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)
  • Nucleotide analog reverse transcriptase inhibitors (NtARTIs or NtRTIs)
• Entry inhibitors inhibit the viral entry into the cell interacting directly with the viral receptor and avoiding the fusion of the viral membrane with the target cell membrane.

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.

Immunity

About 10% of all Europeans carry a polymorphism of CCR5, a cell surface receptor that plays a role in HIV-1 infection (particularily the R5 strain). People with this mutation have a decreased risk of infection with HIV-1.

Common myths regarding HIV

HIV budding from an infected human immune cell

• "AIDS and HIV are the same thing".
  • HIV is the virus which damages the host such that it leads to immunedeficiency. A state of immunedeficiency is necessary for the condition known as AIDS. Certain types of AIDS defining illnesses must be present for a person to be diagnosed as having AIDS. A person can be infected for years without developing AIDS. Having an HIV infection does not mean you have AIDS.

• "HIV only affects homosexuals and drug users".
  • HIV can infect anyone. Babies, women, seniors over 50, teens, Blacks, Whites, Asians, and Hispanics can all contract HIV.

• "There is no risk to two people already infected to have unprotected sex".
  • For years HIV reinfection (or superinfection, as it is sometimes called) has been theorized as a consequence of unprotected sexual encounters between two HIV infected people. Simply put, reinfection occurs when a person living with HIV gets infected a second time while having unprotected sex with another HIV infected person. Reinfection has been demonstrated in laboratory studies as well as in animal trials. And for years, proof that it could happen in real-life situations has been hard to come by. But now, compelling evidence has surfaced in human case studies that has confirmed our fears that HIV reinfection can occur and can be very problematic for HIV infected people.

• "People over age 50 don't get HIV".
  • The number of people over age 50 who are newly diagnosed with HIV infection is growing.

• "A HIV positive woman can't give birth to a healthy baby".
  • HIV is sometimes transmitted from mother to unborn child, but not always. The risk is at least 20-30% for maternal-fetal transmission of HIV. Delivery via cesarean section and antiretroviral drugs, taken during pregnancy, reduce the chance of mother to child infection. Post-partum infections via breastfeeding are also a problem, especially in the Third World where infant formula may not be available.

• "A single identifiable person brought HIV to North America"
  • See Patient Zero.

Life Cycle of HIV

HIV 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. 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 bond to CXCR4.

Once HIV has bound to the CD4+ T-cell a viral structure 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.

Since the host T-cell does not process RNA into proteins the next step is to generate DNA from the HIV RNA using the reverse transcriptase enzyme to perform reverse transcription. 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.

Once the host cell starts to produce proteins from the pro-viral DNA the HIV-supplied protease enzyme must cleave the nascent HIV proteins in order for them to be assembled into HIV virons. The virons leave the cell by budding through cholesterol rafts on the host cell surface.

External links

• AIDS/HIV Education (http://www.ericdigests.org/pre-9212/hiv.htm)
• HIV/AIDS Education in Teacher Preparation Programs (http://www.ericdigests.org/1997-3/hiv.html)
• Continuing medical education about HIV for healthcare providers (http://www.cmeonhiv.com)

Topics to be covered

To be written:

• shape
• enzymes
• structure proteins

Reference

• Kahn JO, Walker BD. Acute Human Immunodeficiency Virus type 1 infection. N Engl J Med 1998;331:33-9.

See also

• HIV test
• List of HIV-positive people
• HIV positive people
• Criminal Transmission of HIV

External links

• Genome (HIV-1) (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NC_001802)
• Genome (HIV-2) (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NC_001722)
• "The Molecules of HIV" information resource (http://www.mcld.co.uk/hiv/)

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