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Full name: Human Immunodeficiency Virus

Synonyms: LAV (lymphadenopathy-associated virus), HTLV III (human T-cell lymphotropic virus-type III), ARV (AIDS-associated retrovirus), AIDS virus
German: HI-Virus

1 Definition

The HIV is a RNA virus belonging to the group of Lentiviridae within the family of Retroviridae, which causes an HIV disease that typically leads to AIDS in the late stage. So far, two types of HIVs are known, HIV 1 (inclusive of subtype 0) and HIV 2. HIV is the best examined and most researched of all viruses.

2 History

Most sources differ on the history of HIV. The most widely accepted expert opinion concludes that the transmission of the virus took place from primates to humans during the first half of the 20th century. The reason for this assumption lies in the similarity of the virus found in these animals, mainly the SIV (simian immunodeficiency virus), which triggers symptoms in primates that are similar to those of humans infected with HIV. </br> There is a general assumption that the first cases of HIV infections occurred in Africa. The disease can be traced to Haiti from Africa and from there later to the US, where the first HIV cases were described in 1981. The first infections in Europe were reported in 1982. Later examinations of blood samples taken in 1959 in the Congo region revealed HIV fragments.

Luc Montagnier was the first to isolate HIV in 1983 from a patient with symptoms of a lymphadenopathy; he named the virus LAV (lymphadenopathy-associated virus). Months later the same virus was again isolated by Robert Gallo, who named it HTLV III (human T-cell lymphotropic virus) due to its similarity with the already known lymphotropic retroviruses. Both researchers entered into an argument about the initial description of the virus, which was settled only after a joint conference in Paris.

First tests for HIV occurred in 1985; they were based on the detection of virus-specific antibodies in the blood. This enabled the tests for blood products contaminated by viruses. The attachment of the virus to the CD4 receptor of T-cells and macrophages was proven the same year. In 1986, type II HIV was discovered and AZT, the first life-prolonging drug, was launched in the market.Since 1996, a combination therapy with several virostatics is the standard treatment for AIDS.

3 Structure

HIV has a diameter of approximately 100 nm and on electron microscopic pictures looks almost round.

3.1 Core

Two copies of the virus genomes exist in the core of the virus in the shape of single-stranded RNA molecules, to which proteins, mainly the nucleocapsid protein p9, are bound. The three main proteins of the virus, reverse transcriptase, virus protease and integrase are also associated with the nucleic acid. </br> A capsid formed by the proteins p24 and p7 encases the HIV’s genome.

3.2 Envelope

During the release of the virus from the host cell, the capsid is typically covered by a virus envelope of phospholipids of the host cell membrane. Viral matrix proteins, mainly protein p17, are bound to these membrane lipids. </br> Besides residual cellular membrane proteins, two viral glycoproteins are anchored in the lipid double layer, the transmembrane protein gp41 and the extracellular protein gp120, which is significant for the infection of somatic cells by the virus.

4 Virus genome and gene products

The genome of HIV contains only nine genes, so that the virus largely relies on cellular enzymes and substrates for the replication and transcription of its proteins.

4.1 Structure of the viral nucleic acid

The virus genome consists of two copies of a positive strand RNA chain, which exists in the core associated with proteins, but cannot directly function as mRNA in the transcription. There are the so-called LTR regions (long terminal repeats) at the 5' and 3' ends of the RNA, which act as strong promoters in the formation of viral gene products; the HIV genes that encode for all structurally and enzymatically effective proteins are in between.

4.2 Genes of the HIV

According to the findings published so far, the RNA of HIV possesses nine genes, but only three genes (gag, pol, env) encode for proteins that are passed on. The other six genes (Rev, Nef, Tat, Vif, Vpr, and Vpu) encode for regulation factors of genetic processes.

  • gag (group specific antigen): The gag gene encodes for the proteins of the capsid, p7, p24 and p17.
  • pol (polymerase): The information for all enzymatic proteins of the virus, for reverse transcriptase, protease and integrase, can be found in the area of the pol gene.
  • env (envelope): The env gene contains the genetic information for both glycoproteins of the virus envelope, gp 41 and gp 120.
  • rev (regulator of virion): rev stimulates the expression of viral structural proteins.
  • tat (transactivation of transcription): The tat gene stimulates the LTR-induced production of viral RNA.
  • vif (virion infectivity factor): vif supports the formation of infectious HIVs
  • vpr (viral protein r): vpr supports the formation of virus-specific proteins
  • vpu (viral protein u) vpu is essential for the maturation and release of the virus
  • nef (negative factor) nef inhibits the transcription of viral genes and the replication of the RNA.

4.3 Genomic mutations

HIV is only equipped with a part of the proteins necessary for the process of the viral reproduction cycle. Therefore it depends on the replication and the transcription machinery of the host cell. After infecting a cell, the RNA genome of the virus is transcribed to DNA and integrated into the genome of the host cell (see below: pathomechanism). According to statistics, reverse transcriptase and human RNA polymerases incorrectly incorporate approximately every 10,000th base. Since both enzymes have no chance of proofreading or repairing mismatches, they cause incorrect information with a probability of 10-4, so that each newly synthesized nucleic acid contains statistically 3 to 5 errors. Thus over time diverse mutants of HIV develop, some of which can reproduce and infect other cells. But they show differences in the amino acid sequence of their proteins. In the course of the HIV disease, the structure of the viruses continuously alter and thereby also inhibits an effective immune defense.

Genomic mutations can generally lead to more aggressive virus variants. In early 2005, a new variant of HIV was found in an HIV patient in New York, which causes a clearly faster course of the disease and has a multiple resistance against HIV therapeutics ("Super-HIV"). This virus mutation seems to be able to simultaneously utilize the cytokin receptors, CCR5 and CXCR4 (X4), to bind to the virus.

4.4 Virus proteins

The virus genome mainly encodes, besides the aforementioned regulatory proteins, for structural proteins and three enzymes that become part of the particle after the release of the virus.The structural proteins have abbreviations (p for protein, gp for glycoprotein) and numbers which indicate their molecular weight in kilodalton:

  • Structural proteins (encodes in the genes gag and env)
    • p17: p17 is a matrix protein inside the virus envelope.
    • p24: Protein p24 is the main component of capsid.
    • p9: p9 is part of the viral nucleocapsid.
    • gp41: The glycoprotein formed by the precursor gp160 and gp120 transmembraneously pervades the virus envelope.
    • gp120:glycoprotein 120 is positioned outside the virus envelope and associates with gp41, with which it is transcribed.
  • Enzymes (encodes in the pol gene)
    • p66 (reverse transcriptase): Contrary to the "central dogma of cell biology," reverse transcriptase is able to transcribe RNA to DNA. It uses human tRNA as a matrix. After the synthesis of DNA, the reverse transcriptase breaks down the RNA and synthesizes the complementary DNA strand.
    • p11 (protease): The protease catalyzes the hydrolytic cleavage of the viral proteins, which are translated in groups into functional units. The protease initially cleaves itself from the polypeptide chain, encoded by the pol gene, and then cleaves the reverse transcriptase from the integrase.
    • p32 (integrase): The integrase is able to incorporate the DNA double strand synthesized by the reverse transcriptase into the genome of the host cell.

5 Infection mechanisms

According to current knowledge, the viral cycle occurs in seven phases, which the virus has to traverse from the infection of the host cell to its renewed release.

5.1 Virus adsorption

After the virus invades the bloodstream of a human being, it can attach with its surface protein gp120 to the CD4 receptor of various blood cells, mainly CD4+ T-cells and macrophages. But generally all cells expressing the CD4 receptor are potential host cells of the virus; this therefore also applies to certain microglia cells of the CNS and cells of the gastrointestinal tract.

5.2 Virus fusion

After the HIV is bound to its host cell, an indentation is formed within the cell membrane. Through the interaction of additional receptors, mainly of the cytokin receptors CCR5 and CXCR4, the virus can bind more closely and fuse its membrane with the lipid double layer of the host cell. Thereby the capsid is released into the cytosol.

5.3 Release of viral RNA

In another process called uncoating, the capsid releases the virus genome within the cytoplasms of the host cell. The mechanisms relevant for it are largely still unknown.

  • Note: It is known that the HIV cannot replicate in most primates. They are naturally protected from HIV by the expression of the protein TRIM 5α, but not from SIV, a virus in monkeys similar to HIV.

5.4 Reverse transcription

The proteins contained in the virus capsid are released together with the virus RNA. The reverse transcriptase introduced in the cell immediately starts with the synthesis of the complementary DNA strand and after that with the formation of DNA double strands, which form a circle. As a primer, it uses human tRNA molecules that exist in the cytoplasm or have been carried along from lysed cells as components of the capsid.

  • Note: Even if the HIV genome consists of positive RNA strands, it cannot serve as a matrix for the protein biosynthesis (mRNA), but has to be transcribed in DNA and integrated in the genome of the host cell.

5.5 DNA integration

The annular DNA double strands are catalyzed by the enzyme integrase and presumably integrated at random in the genome of the host cell; thereby the HIV exists as the so-called provirus. Its genes can be read now from the human RNA polymerase II, while the LTRs act as strong promoters.

  • Note: The process from the virus’ attachment to the host cell up to the integration of the genome takes approximately ten hours. After the integration of the viral DNA it can take years before the production of viral components takes effect and the cell is eventually lysed by the release of new viruses. It is so far unknown, how this so-called latency period ends, but however, the transcription factor NFκB is ascribed a function in the triggering of productive cycles.

The immune system can be compromised even in the time of latency; its cause is also unknown yet. Once large amounts of immune-competent cells are affected, it marks the onset of AIDS.

5.6 Biosynthesis of viral proteins

After the latency phase ends, the host cell begins with the transcription of viral genes, whereby the regulator proteins encoded by the HIV genome and host-inherent transcription factors participate in the regulation. The viral proteins are translated by the formed mRNA and posttranslationally modified. Glycosyltransferases of the cell provide for the glycosylization of the envelope proteins gp41 and gp120, while the protease of the virus releases both proteins from the precursor gp160. It also cleaves the gene product of pol into the three enzymes protease, integrase and reverse transcriptase.

5.7 Assembling and maturation

Due to mechanisms not yet understood, complexes of viral proteins are formed at certain sites of the cell membrane, which cause the budding of the membrane. Eventually mature virus particles form, which contain all proteins necessary for the continuation of the infection cycle. Through lysis of the host cell, they are again released into the blood and bind once again to CD4+ cells.

5.8 Resistance

In patients with a certain mutation of the cytokin receptor CCR5, HIV cannot easily replicate, since the virus fusion is hampered. In carriers of heterozygote traits, the infection is exacerbated, and in homozygotic persons a natural resistance against HIV seems to exist.

6 Mechanisms of immunosuppression

The exact mechanisms of HIV’s effect on the immune system are largely unknown. It is established that after an infection with HIV, the immune system can reduce the viral load in the blood almost to zero with the help of the primary immune response. However, HIVs survive in T-helper cells and other cells and elude the immune system in a way not yet fully understood. The infected cells presumably do not express viral proteins on their surfaces and therefore cannot be recognized as infected. Due to the T-cell inhibition, the secondary immune response only has a weak impact and thus only plays an inferior role in the resistance of HIV.Paradoxically, the number of T-helper cells in the blood sinks more than would be expected from the virus titers. It is assumed that there exist other mechanisms besides the affection of these cells by the HIV, which cause the suppression of the T-cell induced immune response.

7 HIV infection

The HIV infection has become one of the most frequent diseases worldwide. In the list of the most frequent disease-related causes of death, AIDS caused by the virus is on the fourth position.

7.1 Epidemiology

Since the discovery of the HIV, approximately 60 million people have been infected. In 2002, 42 million of them were alive, 60,000 of them in Germany. Every year, approximately 5 million people become infected with the virus, and 800,000 of them are children below 15 years of age. Every year, approximately 2000 people become newly infected with HIV in Germany.Large parts of Africa and Southeast Asia are considered high-risk areas; in some countries of these regions, 30 to 50% of the population are probably infected.

7.2 Incidence of the virus

In the human organism, HIV can be detected in most body fluids. Besides blood and lymph, the virus is also present in saliva, vaginal secretion, ejaculate and mother’s milk. The HIV presumably does not cross over to the placenta, but can be transmitted to the newborn child through blood contact during birth.

7.3 Transmission routes of the virus

HIV is very sensitive to air exposure and disinfectants, and a transmission by [[aerosol infection|aerosol] infection or indirect infection can therefore be almost completely excluded. </br> A direct contact with body fluids, predominantly blood and genital secretions, mainly leads (statistically however only in rare cases) to an intake of the virus and thus to an HIV infection.Typical transmission routes are sexual intercourse, use of infected syringes and medical devices, intravenous transmission of blood products and perinatal transmission.

8 Molecular basics of anti-HIV therapy

By now, a number of antiretroviral drugs are available, which take effect at different stages in the reproduction cycle of HIV (See also: virostatics):

8.1 Inhibition of reverse transcriptase

The inhibition of reverse transcriptase prevents the transcription of the virus genome into DNA. A potential formation of new viruses is inhibited. Today, a range of medicines is available for the inhibition of reverse transcriptase, mainly analogs of nucleosides, which can be used as substrate and respectively lead to the inhibition of the enzyme and termination of the DNA chain’s formation:

8.2 Inhibition of protease

The protease cleaves amino acid chains that are translated into viral genes into functional proteins. The inhibition of the enzyme prevents this, so there is a lack of gene products for the assembly of new viruses.</br> Common preparations for the therapy of an HIV infection are as follows:

Protease inhibitors typically have severe side effects, since they interact with cytochrome P-450 enzymes of the liver, and thereby influence the decomposition of other substances through the P-450 pathway. The therapy of an HIV disease does not typically follow a standard. The administration of medicines follows certain principles. Several drugs are combined to delay the formation of resistant viruses (HAART). The previously favored dogma "hit early, hit hard" was recently somewhat qualified, since resistances were observed in some patients already at an early stage, and the medicines often had massive, unpleasant side-effects.

  • Note: The typically applied combined drugs led to the obligatory intake of large numbers of tablets, so that the compliance of HIV patients decreased over time due to the high amount of medicines alone. Thus, new combination drugs are offered, which remarkably reduce the number of tablets, but contain the same dosage of active agents.

9 Prophylaxis

The prophylaxis of HIV infection plays a significant role today, since the therapy is still insufficient. Latex gloves are routinely used while working with blood or handling blood products. The testing of stored blood for virus infection are standard procedure. Safer sexual intercourse through the use of condoms is today considered the only prophylactic measure against a sexually transmitted infection, especially among risk groups (homosexuals, prostitutes and promiscuous people).

10 HIV tests

The standard HIV test is based on the detection of antibodies in the blood active against proteins of the HIV, particularly against the p24 protein of the virus capsid in the ELISA procedure. In a positive test result, usually a proof of viral proteins is carried out, followed by a Western blot to avoid false positive results. By this, the probability of a falsely diagnosed HIV infection can be reduced to one in 20,000 cases. Another analysis for testing HIV that is not carried out as a standard procedure due to costs is the proof of viral RNA with RT-PCR followed by quantification procedure.

  • Note: Since the first viral proteins can be detected in the blood only after approximately 6 to 8 weeks, one has to wait during this period after exposure, before a significant test can be carried out.

11 Outlook

A sufficient therapy or even healing is so far out of reach. But, due to the introduction of efficient medicines, the awareness for the danger of an HIV infection has decreased in the population. In recent years, a slight rise of new infections can be observed.

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