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Human Immune Deficiency Virus (HIV) Amfar and In 1983, the laboratory of Luc Montagnier at the Pasteur Institute isolated a retrovirus and called it lymphadenopathy-associated virus. Subsequently the laboratory of Robert Gallo at the National Cancer Institute identified a retrovirus and called it HTLV-II. Subsequently it was recognized that these isolated viruses were all of which was latter named human immunodeficiency virus or "HIV" in 1986. There are 2 known strains of HIV. Click Here for Techniques in HIV Research The virus infects human, chimpanzees and the pigtailed macaque. But it causes immune suppression only in human and the pigtailed macaque. Among viruses, HIV is known as a retrovirus. Morphological wide, HIV appears like a corn kernel under the microscope. Viral Structure: RNA genome: The genome of the HIV virus consists of 2 identical RNA molecules. The HIV genome is about 10 kb in length and organized similarly to that of other retroviruses. The sequence is flanked by 2 long terminal repeates (LTRs) (which are important in transcriptional control) The 5' LTR contains the enhancer promoter sequences for viral transcription and the 3' LTR contains the polyadenylation signal. From 5' to 3' the viral genome contains the following genes: gag (group specific antigen) proteins which make up viral capsid and are recognized by specific antigens of immune system of infected organism. The gag gene encodes a precursor polyprotein that is cleaved by pol-encoded protease to yield p24, p7, p9 and p17. P17 and p24 around the RNA genome with 2 layers forming a cylindrical protein core. pol (polymerase) a gene which encodes for a polyprotein which is cleaved to generate 3 enzymes: reverse transcriptase, protease and integrase. HIV protease: plays an essential role in HIV replication, performing the psttranslational processing of the Gag and Gag-Pol proteins into the functional core proteins and viral enzymes. Inhibition of this enzyme leads to the production of immature, noninfectious viral progeny, blocking further rounds of infection. Structural and Regulatory Proteins HIV Entry, Integration and Expression Tests for Virus infection: --PCR Viral genome can be applied. Even allows quantification of virus. But due to high sensitivity of PCR can rarely have false negatives particularly where concentration of virus very low (as where virus is integrated into cell). HIV virus concentration decreases after infection and gets so low that often hard to detect even with PCR. PCR can also result in false positives. --syncytia formation --ELISA: Viral antigens are absorbed onto a solid phase and the patient's serum is added. Unbound antibody is washed away and then enzyme-conjugated goat antihuman immunoglobulin is added. After washing excess reagent away, the substrate for the enzyme is added. --Western Blot Assay:HIV proteins are separated by electrophoresis and then transferred to a nitrocellulose membrane. Patient's serum is added to the nitrocellulose and allowed to react. Radiolabeled goat antihuman immunoglobuline is then added. The presence of radioactive bands corresponding to the molecular weight of the antigens indicates the presence in the patient of antibody to HIV. Stages of HIV Infection Acute Infection During this period the mucosa are the dominant site of infection. The gastointestinal tract and other mucosal tissues contain at steady state at least half of the body's T cells. These T cells are predominantly CCR5+, and many of them are in an activated state. During acute HIV infection, the virus rapidly multiples and propagates in the lymphoid compoent of mucosal tissues, thereby profoundly affecting the immune system soon after infection. In macaques infected with SIV, intestinal CD4+ T cells are almost entirely depleted within three weeks after infection. During the actue phase and into the chronic pahse of infection, the sites of HIV replication begin to include other peripheral lymphoid organs. High levels of HIV accumulate in lymph node follicular dendritic cells, which are of epitthelial origin and therefore ditinct from the dendritic cells of hematopoietic origin. The virus persists mainly as a latent reservoir in memory CD4+% (CD45RO+) cells which possess the inherent ability to survive for a rpolonged period of time. HIV Prevention, Decontamination and Safety measures: Prevention: One possibility is to target CCR5 and CXCR5 which serve as co-receptors for HIV entry. Recently, an array of small molecule inhibitors that prevent HIV entry into cells have been developed, which many in clinical trails and one having been licensed in 2003. Potential microbicides for HIV can be placed into one of three categories: (1) compounds that inhibit virus infection nonspecifically. Most microbicide candidates tested to date fall within this category. The first candidate microbicide for HIV to reach phase III clinical trails was the spermicidal detergent nonxynol-9. Although the compound inactivates HIV in vitro by disrupting the outer viral membrane, it failed to prevent sexual transmission of the virus in vivo. In fact, women who used nonoxyl-9 containing gels had a higher rate of infection by HIV, most likely because the detergent disrupted the membranes of the epithelial cells in the genital tract which otherwise serve as an important barrier to virus infection. (Davis et al 2004). (2) compounds that specifically target the virus. Passive administration of neutralizing antibodies can convert sterilizing immunity to macaques who are vaginally challenged with virus, provided the antibodies are present within several hours of virus application. Likewise, a vaginally applied neutralizing antibody prevented infection of macaques. Although promising, the greatest drawbacks to the use of moncolonal antibodies is their cost and the structural variability of the viral Env protein to which they bind. Only a handful of broadly cross-reactive, neutralizing antibodies have been developed over the past 20 yr and none of these recognize all virus strains. Recently, small molecule inhibitors that prevent HIV entry into cells have been developed with many in clinical trials and one licensed in 2003. Since viral attachment to and entry into host cells is the first step in establishing an infection, this process is particularly attractive target for microbicides. However, there are multiple ways by which HIV can infect target cells i n the genital mucosa. . Second, even if all host receptors for viral entry are blocked, HIV may be capable of evading these inhibitors by hitching a ride on DCs. Decontamination: Low pH has been reported to inactivate HIV. For example, dilute acetic acid (pH 2.8) (white vinegar; Heinz Inc.) has been reported to inactivate HIV (Martin et al., Disinfection and inactivation of the human T lymphotropic virus type III/lymphadenopathy-associated virus. J. Infect. Dis. 152:400-403 1985). Long-Term Nonpreogressors: It is clear that there is a significant percentage (about 5%) of HIV infected people who do not experience progression of HIV disease and whose CD4+ T cell counts remain stable and within normal range for many eyars. There LTNP have low but ravirable degrss of virus trapping in lymph nodes, whereas virus expressing cells are only rarely seen. Levels of all virologic parameters, including plasma viremia, viral burnen (i.e., frequency of mononuclear cells containing HIV DNA) and virus expression are lower (20-40 fold) compared to progressors. However, HIV was generally isolated by coculturing lymph node mononuclear cells with PHA activated mononuclear cells from normal donors, indicating that the virus in most LTNP is replicaiton competent and infectious. HIV models: There is a mouse model for AIDS called murine AIDS (MAIDS) which is caused by the murine leukaemia virus (MLV). MAIDS develops in T-cells that carry the CD4 receptor in their cell membranes. More Information: Cross-references to this Web Site: HIV Treatment Strategies HIV abnormalities and symptoms Web Sites: NIAID Division of AIDS (DAIDS) Home Page UN-AIDS HIV molecular immunology database Companies which are involved with HIV |
