Role Of Viral Reservoirs In Pathogenesis Of HIV Disease

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The use of effective antiviral therapy has led to rapid and sustained suppression of HIV replication and has dramatically improved the clinical outcome in the vast majority of infected individuals who are treated optimally. However, it has not been possible to eradicate HIV in infected individuals receiving effective antiviral therapy mainly due to the persistence of various viral reservoirs. Among those, a pool of latently infected cells in the resting CD4+ T cell compartment has been one of the most extensively studied and is considered to be a major impediment to HIV eradication. The extremely long intrinsic half-life of such a latent HIV reservoir may make eradication of the virus all but impossible in patients receiving currently available antiviral therapy. However, studies conducted over the past several years suggest that low levels of on-going viral replication persist and consequently prolong the overall half-life of HIV in patients receiving antiviral therapy. In the past year, we investigated the presence and status of residual HIV in a cohort of patients who had received uninterrupted antiviral therapy for up to 9.1 years; therapy that rendered them consistently aviremic. We demonstrated the persistence of replication-competent virus in CD4+ T cells in all study subjects. Surprisingly, substantially higher levels of HIV proviral DNA were found in activated CD4+ T cells when compared to resting CD4+ T cells in the majority of patients whom we studied. Phylogenetic analyses revealed evidence for cross-infection between the resting and activated CD4+ T cell compartments, suggesting that on-going reactivation of latently infected, resting CD4+ T cells and spread of virus by activated CD4+ T cells may occur in these patients. Such events may allow continual replenishment of the CD4+ T cell reservoir and resetting of the half-life of the latently infected, resting CD4+ T cells despite prolonged periods of aviremia.