Human immunodeficiency virus
Le virus de l'immunodéficience humaine (VIH, HIV en anglais) est un rétrovirus infectant l'homme et le conduisant à plus ou moins long terme au syndrome d'immunodéficience acquise (Sida), qui est un état affaibli du système immunitaire qui le rend vulnérable à de multiples infections opportunistes.
Transmis par plusieurs fluides corporels : sang, sécrétions vaginales, sperme ou lait maternel, le sida est aujourd'hui considéré comme une pandémie ayant causé la mort d'environ 25 millions de personnes entre 1981 (date de la première identification de cas de sida) et janvier 2006. Il est estimé qu'environ 1 % des personnes âgées de 15 à 49 ans vivent avec le VIH, principalement en Afrique sub-saharienne.
Bien qu'il existe des traitements antirétroviraux luttant contre le VIH et retardant par conséquence l'apparition du sida, réduisant ainsi la mortalité et la morbidité, il n'existe à l'heure actuelle aucun vaccin ou traitement définitif. La prévention, qui passe notamment par les rapports sexuels protégés et la connaissance de son statut sérologique de manière à éviter les infections d'autrui est le moyen de lutte le plus efficace.
The AIDS epidemic was discovered on June 5, 1981 by the CDC from the United States after the announcement of an increase in the cities of Los Angeles, San Francisco and New York cases of Pneumocystis carinii pneumonia in and of Kaposi sarcoma . Both diseases are unique to infect immunocompromised individuals. The first patients were all homosexuals with the result that this syndrome, which was not yet the name of AIDS, the syndrome is called gay or gay cancer. But in the months that follow, other people are infected, injection drug users and hemophiliacs, showing that the blood, in addition to sexual is the mode of contamination.
The viral origin is preferred, given the modes of transmission then identified. Many viruses are involved, but we realize they are only a consequence. The first discovered human retrovirus, HTLV-1, was seen as the cause of AIDS by the American team led by Robert Gallo.
Beginning in 1982, with the first cases identified in France, French research begins. Willy Rozenbaum, a doctor at the Bichat hospital in Paris, wants to encourage researchers to explore more and before AIDS and figure out what happened. Through the use of Francoise Brun-Vezinet, a fellow doctor, Willy Rozenbaum meeting Jean-Claude Chermann, Francoise Barre-Sinoussi, and Luc Montagnier of the viral oncology unit at the Pasteur Institute. They agree to begin research and January 1983. Willy Rozenbaum sends a sample of a patient with lymphadenopathy, which is identified as an opportunistic disease of pre-AIDS. The sample is cultured and reverse transcriptase activity is identified confirming the presence of a retrovirus. Soon apoptosis appears, the addition of white blood planting then relaunch the activity of reverse transcriptase. An electron microscope examination has led to visualize for the first time the virus.
After making contact with Robert Gallo to exchange information, the team at the Pasteur Institute confirmed that the virus identified in the patient lymphadénopathique not HTLV-1. This new retrovirus is then called Lymphadenopathy Associated Virus (LAV) and the results are published in Science on May 20, 1983. At this stage the relationship between the LAV and AIDS is not clearly established by the team of Luc Montagnier. The team of Robert Gallo published on May 4, 1984 in Science the results of the isolation of a virus, which it considers responsible for AIDS and named HTLV-3. The team of Jay A. Levy in San Francisco did the same on Aug. 24, 1984 and named AIDS-associated retroviruses (ARV). For a time, all three denominations coexist, and a controversy has existed for a while between the American and French teams on the earlier discovery.
The LAV is studied in all its aspects and several points are then shown, as the fact that it is totally different from the HTLV-1 which is an oncovirus pushing T cells to multiply, while the LAV kills. With the cooperation of the CDC, the team at the Pasteur Institute reinforces increasingly the assumption that HIV is the cause of AIDS, which is now regarded as a fact by the scientific community. In January 1985, the sequencing of the LAV is directed by a team from the Pasteur Institute, which publishes its findings in Cell. It was that same year that confirmed that the three virus (LAV, HTLV-3 and ARV) are the same.
The first HIV test are marketed in the year 1985.
On July 18, 1986 are published in Science by the team of Luc Montagnier, in collaboration with doctors Portuguese, the results of the study of a patient from West Africa. The reviews have identified a new type of LAV, the LAV-2 . The sequencing of the new virus is carried out the following year, as well as the development of a screening test.
In 1986, the LAV (as well as other denominations) has been officially renamed the virus in human immunodeficiency (HIV), the LAV-1 becomes HIV-1 and LAV-2, HIV-2.
The international community is aware of the seriousness of the epidemic, which is fast becoming epidemic and that is October 26, 1987 the UN General Assembly passed a resolution calling on all States and the UN agencies to cooperate in fight this pandemic. Since the fight against HIV / AIDS has become a priority for the United Nations through its programme UNAIDS, as well as many governments. The scientific community is also very active in order to develop a vaccine, causing HIV virus most studied so far.
Although AZT has been used since 1986 to combat HIV, it was not until the mid-1990's for the market as the most effective treatment against HIV replication. These treatments, known as triple therapy, a combination of drugs to combat HIV on many fronts at once. The development of biological test for estimating the viral load has greatly contributed to the effectiveness of these treatments, as can be amended accordingly triple to make it as effective as possible.
A long incubation period and consequently a slow onset of the disease (hence the root of the name from the Latin lenti, meaning slow).
It is an aspect generally spherical with a diameter ranging from 90 to 120 nanometers. Like many viruses infecting animals, it has an assistance package consisting of the remains of the membrane of the infected cell. This envelope is covered with two kinds of glycoproteins: the first is the gp41 that crosses the membrane, the second is the gp120, which covers part of the gp41 that comes from the membrane. A strong link exists between gp120 and the CD4 receptor markers on the surface of CD4 cells of the immune system. For this reason, HIV levels reach that cells with this receptor on their surface, which are vast majority CD4 + lymphocytes.
Within the envelope is a protein matrix composed of proteins p17 and still inside the capsid protein composed of p24. It is the latter type of protein, gp41 and gp120, which are used in HIV tests western blot. The nucleocapsid is made for its protein p6 and p7.
The genome of HIV, contained in the capsid, is a single stranded RNA in duplicate accompanied by enzymes that:
* Viral RNA transcribed into viral DNA, p64 reverse transcriptase
* Incorporates viral DNA to cellular DNA, p32 Integrase
* Participating in the assembly of the virus, protease p10. The latter is not present in the capsid, but fleet in the matrix p17
These three enzymes are the principal targets of anti-retroviral treatment, as specific to retroviruses.
The HIV genome is composed of nine genes. The three main gag, pol and env that define the structure of the virus and are common to all retroviruses. The other six genes are tat, rev, nave, lively, and vpr vpu (or vpx for HIV-2) that encode proteins regulating and whose functions are not known with precision.
HIV is present in many body fluids. We found in saliva, tears and urine, but in concentrations sufficient to ensure that cases of transmission are registered. The transmissions by these fluids is considered negligible. By contrast, relatively large quantities of HIV infection were detected in the blood, breast milk, juice, semen, as well as the fluid before ejaculation.
As a result, all three modes of contamination are:
* Unprotected sex, whether heterosexual or homosexual represent the largest share of contamination
* Contact with contaminated materials at:
O health personnel
* MTCT during pregnancy, during birth and during breast feeding. Without treatment and with a natural childbirth transmission rate varies, according to studies, between 10 and 40%. It was during childbirth that the risk of infection are highest (65% of all cases of infection). A treatment and practice a caesarean can reduce this figure to 1%.
The target cells for HIV are those with CD4 receptor on their surface. Thus, CD4 + T lymphocytes, macrophages, dendritic cells, and microglial cells brain can be infected with HIV. Thus, viral replication occurs in several tissues.
The replication of the virus takes place in several stages:
Fixing or attachment to a cell
This step is based on a recognition between proteins on the surface viral gp120 and the CD4 receptors from the cell target. After the union with a CD4 receptor, gp120 changes its configuration and is attracted to a co-receptor should also be present next to the CD4 molecule. About a dozen co-receptor have been identified, but the main ones CXCR4 for CD4 + T lymphocytes and macrophages to CCR5.
The merger, the penetration and décapsidation
This is the second stage of the infection speaking just after the union of gp120 with the co-receptor. This frees the union gp41 protein which binds to the cytoplasmic membrane. By turning in on itself, gp41 draws viral envelope to the cytoplasmic membrane and the fusion of viral and cell membranes occurs through a fusion peptide present in gp41. The HIV capsid then penetrates into the cytoplasm of the cell, once inside the cell, it disintegrates freeing the two strands of RNA and enzymes in it.
Thus, the protein gp120 is responsible for the commitment and gp41 of the merger and penetration within the cell.
The reverse transcription
This step is specific to retroviruses. The latter having the genome RNA rather than DNA, a transcription, "converting" into viral RNA viral DNA is needed. For only the DNA can be integrated into the genome of the target cell. This transcript is produced by the enzyme reverse transcriptase (TI). The TI trail viral RNA and transcribed into a first DNA molecule single-channel, or stranded DNA (-). During the synthesis, RNA matrix is degraded by an activity known as "RNAse H" made by TI. The degradation of the RNA is complete except for two short sequences rich in purines sequences called PPT (polypurine tracts). Both will serve short sequences of primers to TI for the synthesis of the second strand of DNA, the strand (+), using DNA strand (-) as a matrix. The DNA molecule is a final bicaténaire also called DNA double-strand. A special feature of reverse transcriptase is not to be faithful in its transcription and often make mistakes. That's why HIV has considerable genetic variability.
Bicaténaire DNA enters the cell nucleus according to an active process still poorly understood. The nuclear import is a unique characteristic of lentivirus, which are capable of infecting cells in stationary phase, ie whose core is intact. To do this, DNA bicaténaire is at this point in the cycle closely associated with the integrase and other components viral and cellular protein in a complex called complex pre-integration. This complex has the capacity to interact with elements of the membrane to cross the nuclear membrane and enter the cell chromatin. The DNA then randomly integrated into the genome of target cell as a result of the integrase enzyme.
The formation of a messenger RNA
Both DNA of the cell "deviate" locally as a result of RNA polymerase. The nitrogenous bases open kernel will take the complementarity of the sequence and cure into a solid chain: the mRNA (messenger).
The resulting mRNA is heterogeneous. Indeed, it consists of a succession of introns (non-coding parts) and exons (coding). This mRNA must undergo a maturation to be read by ribosomes. With passes of intron excision, leaving the exons.
The translation of RNA
Once out of the nucleus by one of the nuclear pores, the mRNA is read by ribosomes RER (rough endoplasmic reticulum). The mRNA has been done to squeeze between the two sub-units of the ribosome. For each codon (group of three nucleotides) of the mRNA, the ribosome assign one amino acid. These are polymerize as of reading. An initiator AUG codon (adenine-Uracil-Guanine) will start the synthesis while a stop codon (UAA; UGA; UAG) will mark the end.
It occurs in the Golgi apparatus: polypeptides trained and are not yet operational. They must undergo a maturation in the Golgi apparatus.
The structural proteins of the virus (matrix, and nucleocapsid capsid) are produced in the form of polyproteins. When leaving the Golgi, the different proteins are related. The proteins are transported to the membrane where they join the viral membrane glycoproteins. Some join viral RNA viral proteins. The structure of proteins together to form the capsid and the matrix, including the package.
The capsid fate of the infected cell, tearing a portion of the cell membrane (which have been previously set the viral surface proteins (gp120 and gp41)).
The maturation of virus
A viral protease must cleave the bonds of the different structure of proteins (matrix, and nucleocapsid capsid) that are infectious virions. Following the divisions, the virions are ready to infect new cells.
HIV is a virus that has a very significant genetic variability and presents a very mixed. Two types were found:
* HIV-1, the highest in the world
* HIV-2, less infectious than HIV-1 and rampant mainly in West Africa. It includes HIV-2A and HIV-2B.
Within each type exist several groups, which in turn include subtypes.
HIV-1 since 1998 is classified into three groups, each of which corresponds to transmissions independent VIScpz from monkeys to humans:
* Group M (for major group)
* Group O (outlier group)
* Group N (for non-M, non-O group)
The group M with a large predominance of over 40 million people, compared with just over 500 for the group O and only 7 for Group N. Not only did the M group is by far the largest group in terms of number of people infected, but also one that is most prominent in the world by being present on every continent, while the other two groups are only present Central Africa.
The group consists of nine M subtypes or clades (A to D, E to H, J and K). In addition, several recombinant forms (in English circulating recombinant form or CRF), which derive from the multiple infection of a cell by different subtypes, resulting mixtures in the viral genome.
The subtypes and recombinant forms group M are not spread evenly across the globe. Thus, in Europe, the Americas and Australia is the subtype B that is most present, while in Africa it is according to the regions A and C and Asia, according to the regions, Groups C and E.
Although the genetic variability within the same group did not appear to affect significantly the pathogenesis and progression of the infection, it still poses serious problems for the development of an effective vaccine to all groups and strains of HIV, for measurements of viral load and in some cases of HIV test. In the latter case, as well as screening tests based on antigens HIV-1 subtype B and HIV-2 subtype A, may submit a lower sensitivity for the recognition of other sub - types, especially at the primary infection or infection by variants such as HIV-1 group O.
Origin of the variability
The advent of new genetic variants is due to a process of evolution, whose mechanisms are similar to those that explain the evolution of all species alive. The only difference is that the evolution of HIV is extremely fast, which led to the large number of variants today. It explains this great genetic variability of HIV through several reasons:
Mutations frequent random
Among HIV, the rate of change is very important: more than a thousand times greater than in the genome of a human. Here are the reasons:
* Reverse transcriptase, which enables HIV to replicate, is an enzyme with no mechanism for detecting errors of transcription. Mistakes are common and have been estimated at once every 1700 to 10000 nucleotides products. As the HIV genome is composed of just under 10000 nucleotides, there are approximately between one and 10 mutations in viral each cycle.
* The large number of products virions, which is about 10000 per day for each virions infecting a cell. Within the entire body, every two days, from 109 to 1010 virions are renewed. In theory, it can be expected that each of these new virions wears different mutations.
Thus, in a single body there is already infected several genetic variants, representing an almost viral species.
The variability of the viral genome is not the same for all genes, some are more likely to vary than others. Thus, the env gene is the most variable (it is precisely he who code surface proteins gp41 and gp120) while the pol gene is the most conserved.
The genetic recombinations
When a cell is infected by two virions genetically different sequences can recombine, which gives rise to recombinant forms. This process, random, is favoured by risky behaviors because they increase the probability of multiple infections at the same time.
Then there is a process of natural selection. The errors of transcription and recombination produces many virions different from each other. Most of these mutations cause the production of virions unable to replicate properly, which intends to disappear. This significant loss of virions is offset by the large number of virions products. Among the survivors virions are some particularity to be more resistant to attacks by the immune system. This has the effect of making them better adapted to their environment and in the end only resistant virions are present in the body. This leads to more or less short term, an ineffective immune system which causes the immune status of the body if the rate of CD4 + is too low.
Taking a drug treatment for patients infected with HIV also a selection among the population virus. This facilitates the transmission of virions mutants resistant to most drugs. To counter this adaptation of HIV, multiple therapies aimed at "attacking" HIV on several facets at the same time, and limit the possibilities of the virus to adapt to its environment.
Several passages of VIScpz to humans is the reason for the existence of different groups of HIV-1. What is the same for HIV-2, whose ancestor is the VISsmm.
Diagnosis and monitoring infectious
Early diagnosis of HIV infection is important for the proper care of HIV / AIDS. In France, for example, one out of two is detected when the AIDS stage, which multiplies by sixteen risk of dying patient in the first six months of his salary.
In developed countries, tests are performed routinely for blood donations, organ and sperm. The lack of testing has resulted in several contaminations of the masses.
The serological diagnosis is a medical procedure performed in France by a doctor.
The diagnosis to determine the HIV serostatus is done in two steps:
* Screening, in the reference method that requires a detection of antibodies to HIV
* Confirmation that the antibodies detected are associated with HIV infection
The first stage is based on the detection of antibodies produced in response to HIV infection, the HIV antibody. This production of antibodies can be detected with current means an average of 22 days after infection. During this period, known as serologic window, the patient is quite infectious, which poses obvious problems in public health. Once the window serological increased their HIV status can be established.
The first step uses the detection ELISA method, which uses the antibody-antigen reaction to detect the presence of HIV antibodies. To avoid false negatives and so not to miss a case of HIV, the test must have an optimum sensitivity, a combination of viral antigens is used, allowing the detection of antibodies to HIV-1 and anti - HIV-2 (This is referred to as mixed ELISA). The use of two commercial tests of different origins is usually performed to remove the maximum number of false positives from the first step.
If detection is positive, questionable, or discordant, a confirmation is made. The latter seeks to determine whether the antibodies detected are well linked to infection with HIV-1. This requires a specific method, which is designed to eliminate false positive results. It is the western blot method (WB) which is generally used. Again, if the test is questionable or indicates a beginning of seroconversion, a second confirmatory test is performed three weeks later, the time to wait for seroconversion is complete.
This is only the result of a series of such tests that a doctor may declared an HIV-positive patient.
There are other techniques for the detection of HIV infection, such as:
* Antigénie p24: useful when seroconversion has not yet taken place completely. The test becomes negative once seroconversion done, it explains the use of the above procedure as a standard
* The combined method: using the antigénie p24 and the detection of antibodies. This approach is interesting at the very beginning of the contamination, because it reduces the window serological until two to five days, while ensuring the incorporation of persons totally séroconvertis
* Isolation culture: used for newborns of HIV-infected mothers because they are necessarily infected, the antibodies from the mother having been transmitted. The infection is confirmed when reverse transcriptase activity is detected or p24 antigen.
* The detection of viral RNA: one seeks genes gag, pol, or HIV. This method tends to replace the method of isolation by culture for newborns
Once established HIV infection, regular monitoring of the infection must be made to ensure good care of the disease and to better assess the patient's condition. Two factors are taken into account:
* The level of T4 lymphocytes, to define the level of infection
* Viral load, the number of virion in the body, hence the speed of replication of HIV in the body and thus to predict the evolution of the infection
The rate of T4 lymphocytes measure the immune deficiency caused by the presence of HIV. This enumeration is the number of T4 cells in the blood. A normal rate in humans is between 600 and 1200 T4/mm3. It is assumed that:
* 500/mm3 until the patient can live in normal conditions and does not require treatment
* From 350/mm3 the patient must receive antiviral treatment to lower viral load and raise its rate of T4
* Below 200/mm3 immunocompromised and it is very much risk to suffer from multiple opportunistic diseases related to AIDS, there also, the patient must be placed under treatment
The difference between two measurements of viral load spaced in time to evaluate the rate of HIV replication, and hence the progression of the infection. There is a direct link between viral load and the level of immune deficiency, mainly caused by the disappearance of T4 lymphocytes. The viral load is defined by measuring the concentration of viral RNA in the blood. This measure can vary greatly depending on the methods employed for this reason it is important is that all the viral load evaluations are conducted in the same laboratory with the same technique. The number of log10 copies / mL which is used to evaluate the change in time of the viral load. A variation greater than or equal to 0.5 is significant.
It is a combination of these two pieces of information that allow the doctor to determine how to treat their patients.
Read also HIV