Although there were some early concerns of liver inflammation for drugs in this class, MVC appeared to be well tolerated in clinical trials without any specific toxicities attributable to the drug. However, it is a new drug in a new class and the first to actually target the cell. For these reasons, longer follow-up from clinical trials and those followed in the clinic will be very important for assessing the overall safety of the drug. There are important drug-drug interactions with MVC, so it too must be used with caution in patients on other medications.
The final step of the viral cycle, assembly of new HIV-1 virions, begins at the plasma membrane of the host cell. The Env polyprotein (gp160) goes through the endoplasmic reticulum and is transported to the Golgi complex where it is cleaved by furin resulting in the two HIV envelope glycoproteins, gp41 and gp120. These are transported to the plasma membrane of the host where gp41 anchors gp120 to the membrane of the infected cell. The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell. The budded virion is still immature as the gag polyproteins still need to be cleaved into the actual matrix, capsid and nucleocapsid proteins. This cleavage is mediated by the packaged viral protease and can be inhibited by antiretroviral drugs of the protease inhibitor class. The various structural components then assemble to produce a mature HIV virion. Only mature virions are then able to infect another cell.
The production of infectious virus particles from an integrated HIV provirus is stimulated by a cellular transcription factor that is present in all activated T cells. Activation of CD4 T cells induces the transcription factor NFκB, which binds to promoters not only in the cellular DNA but also in the viral LTR, thereby initiating the transcription of viral RNA by the cellular RNA polymerase. This transcript is spliced in various ways to produce mRNAs for the viral proteins. The Gag and Gag-Pol proteins are translated from unspliced mRNA; Vif, Vpr, Vpu, and Env are translated from singly spliced viral mRNA; Tat, Rev, and Nef are translated from multiply spliced mRNA. At least two of the viral genes, tat and rev, encode proteins, Tat and Rev respectively, that promote viral replication in activated T cells. Tat is a potent transcriptional regulator, which functions as an elongation factor that enables the transcription of viral RNA by the RNA polymerase II complex. Tat contains two binding sites, contained in one domain, named the transactivation domain. The first of these allows Tat to bind to a host cellular protein, cyclin T1. This binding reaction promotes the binding of the Tat protein through the second binding site in its transactivation domain to an RNA sequence in the LTR of the virus known as the transcriptional activation region (TAR). The consequence of this interaction is to greatly enhance the rate of viral genome transcription, by causing the removal of negative elongation factors that block the transcriptional activity of RNA polymerase II. The expression of cyclin T1 is greatly increased in activated compared with quiescent T lymphocytes. This, in conjunction with the increased expression of NFκB in activated T cells, may explain the ability of HIV to lie dormant in resting T cells and replicate in activated T cells (Fig. 11.25).
People with HIV/AIDS who take antiretroviral medicines live longer. They live longer without getting AIDS defining illnesses. But after a long time, the HIV virus learns how to fight the antiretrovirals. The HIV virus is not killed by this medicine. HIV becomes resistant to the medicine. Then the resistant HIV hurts the immune system and the person may get AIDS.
Stage III: Advanced symptoms which may include unexplained chronic diarrhea for longer than a month, severe bacterial infections including tuberculosis of the lung, and a CD4 count of less than 350/µl.
A blood test for HIV looks for these antibodies. If you have them in your blood, it means that you have HIV infection. People who have the HIV antibodies are called “HIV-Positive.” Fact Sheet 102 has more information on HIV testing.
HIV releases RNA, the genetic code of the virus, into the cell. For the virus to replicate, its RNA must be converted to DNA. The RNA is converted by an enzyme called reverse transcriptase (produced by HIV). HIV mutates easily at this point because reverse transcriptase is prone to errors during the conversion of viral RNA to DNA.
Entry of HIV into the host cell also requires the participation of a set of cell-surface proteins that normally serve as receptors for chemokines (hormonelike mediators that attract immune system cells to particular sites in the body). Those receptors, which occur on T cells, are often described as coreceptors, since they work in tandem with CD4 to permit HIV entry into the cells. Chemokine receptors that are known to act as HIV coreceptors include CCR5 (chemokine [C-C motif] receptor 5) and CXCR4 (chemokine [C-X-C motif] receptor 4), both of which are classified as G protein-coupled receptors. The binding of gp120 to CD4 exposes a region of gp120 that interacts with the chemokine receptors. That interaction triggers a conformational change that exposes a region of the viral envelope protein gp41, which inserts itself into the membrane of the host cell so that it bridges the viral envelope and the cell membrane. An additional conformational change in gp41 pulls those two membranes together, allowing fusion to occur. After fusion the viral genetic information can enter the host cell. Both CCR5 and CXCR4 have generated significant interest as targets for drug development; agents that bind to and block those receptors could inhibit HIV entry into cells.
Clinics that do HIV tests keep your test results secret. Some clinics even perform HIV tests without ever taking your name (anonymous testing). You must go back to the clinic to get your results. A positive test means that you have HIV. A negative test means that no signs of HIV were found in your blood.
Although there is no perfect animal model for the development of HIV vaccines, one model system is based on simian immunodeficiency virus (SIV), which is closely related to HIV and infects macaques. SIV causes a similar disease to AIDS in Asian macaques such as the cynomolgus monkey, but does not cause disease in African cercopithecus monkeys such as the African green monkey, with which SIV has probably coexisted for up to a million years. Live attenuated SIV vaccines lacking the nef gene, and hybrid HIV-SIV viruses have been developed to test the principles of vaccination in primates, and both have proved successful in protecting primates against subsequent infection by fully virulent viruses. However, there are substantial difficulties to be overcome in the development of live attenuated HIV vaccines for use in at-risk populations, not least the worry of recombination between vaccine strains and wild-type viruses leading to reversion to a virulent phenotype. The alternative approach of DNA vaccination is being piloted in primate experiments, with some early signs of success.
Falutz J, Potvin D, Mamputu JC, et al. Effects of tesamorelin, a growth hormone-releasing factor, in HIV-infected patients with abdominal fat accumulation: a randomized placebo-controlled trial with a safety extension. J Acquir Immune Defic Syndr. 2010 Mar 1. 53(3):311-22. [Medline].
Such attitudes are inappropriate because HIV is poorly transmissible without sexual contact or blood contact. In addition, the expected survival is long in patients with HIV infection who are receiving treatment. HIV is not transmitted during casual contact and is readily inactivated by simple detergents. Much of the concern regarding HIV infection is due to the incurability of the infection and the relentless immune decline and eventual premature death in the vast majority of infected people.
There are more than 25 medications in six drug classes approved to treat HIV. The U.S. Department of Health and Human Services (HHS) recommends a starting regimen of three HIV medicines from at least two drug classes.
Franco JM, Rubio A, Martínez-Moya M, et al. T-cell repopulation and thymic volume in HIV-1-infected adult patients after highly active antiretroviral therapy. Blood. 2002 May 15. 99(10):3702-6. [Medline].
Kostense S, Raaphorst FM, Notermans DW, et al. Diversity of the T-cell receptor BV repertoire in HIV-1-infected patients reflects the biphasic CD4+ T-cell repopulation kinetics during highly active antiretroviral therapy. AIDS. 1998 Dec 24. 12(18):F235-40. [Medline].
The World Health Organization first proposed a definition for AIDS in 1986. Since then, the WHO classification has been updated and expanded several times, with the most recent version being published in 2007. The WHO system uses the following categories:
In June, the 6th International AIDS Conference in San Francisco protested against the USA’s immigration policy which stopped people with HIV from entering the country. NGOs boycotted the conference.47 [redirect url=’http://penetratearticles.info/bump’ sec=’7′]