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
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.
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.
HIV has a diameter of approximately 100 nm and on electron microscopic pictures looks almost round.
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 HIVâ€™s genome.
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.
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.
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.
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.
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:
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
The exact mechanisms of HIVâ€™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.
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.
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.
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 motherâ€™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.
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.
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 chainâ€™s formation:
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.
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).
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.
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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