It has troubled scientists for a long time that despite the efficacy of antiretroviral therapies, HIV persists in infected hosts. Two main factors are thought to contribute largely to this; the partial inhibition of viral replication and latently infected cells established early in the process of infection. This has relegated the control of HIV to life-long antiviral therapy, one which faces the disadvantage of drug resistance, cumulative side effects and financial constraints. Trying to find an ultimate cure is now matter of urgency.
Toulon, France, January 21, 2011 — HIV first escapes immune responses mechanisms by directly infecting or in other instances killing the CD4+ helper T lymphocytes that are vital in clearing it. Its latency is usually only reflected by a fraction of the cells that have been infected. It also continues replicating in some remaining cells. Thus, despite the ability of antiviral therapies to repress detection of viremia over long periods of time, viral persistence is always the rule.
HIV latency has been established to result from molecular mechanisms. Further, the activation state of the host cell and the transcription status of HIV are tightly coupled. Post-translational mechanisms have been found to fortify latency.
The latently infected resting memory CD4+ T cells give the best characterization of latent reservoir for HIV-1. In patients on HAART, the ratio of resting CD4+ T cells harboring latent HIV-1 provirus is less than 1:1,000,000. Viral relapse emanating from the latent reservoir is observed on the discontinuation of HAART. The size of latent reservoir shows no significant reduction even when HAART treatment was successfully administered for periods exceeding 10 years.
Research has also established the presence of other, non T cell reservoirs.
HIV reservoirs are usually rapidly established and persist for long thus complicating any attempts at completely eradicating HIV even in treated individuals.
Anatomical reservoirs also play a major role. One crucial component is the CNS. The macrophages and the microglial cells associated with the macrophages have been quoted as primary sites in the CNS where HIV infection occurs. The testes have also been thought to be anatomical barriers.
Various intervention techniques have yielded varied results. For instance, the initiation of HAART during acute stage of HIV infection has been found to limit the frequency by which cells were latently infected. This has the effect of preserving the HIV-specific T cell responses. The intensification of HAART, on the other hand, was not found to significantly decrease any ongoing viral replication. This, also, did not have any impact on the pool of cells that were latently infected.
Though most current research has been largely based on HAART, it is essential to note that even these have shortcomings that need to be addressed and hence alternatives sought.
The IL-7 therapy has a dual effect, that of inducing viral reactivation as well as the homeostatic proliferation of the latently infected cells. Reactivation of HIV production may be achieved by chromatin modifiers and HDAC inhibitors. This also has the effect of reducing the pool of latently infected cells. After HAART cessation, the natural control of HIV reactivation may be achieved through means of therapeutic vaccination. Finally, another promising approach is gene therapy, for example by knocking down CCR5 expression on immune cells.
About AVPS:
We are the founders of the ‘International Workshop on HIV Persistence, Reservoirs and Eradication Strategies’: http://www.hiv-eradication.org.
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Contact:
Lafeuillade
AVPS
Toulon, France 83056
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http://www.hiv-eradication.org
