Project 1: Analysis of 2nd phase decay in persons living with HIV

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Summary – Project 1 The development of an accurate assay for plasma HIV-1 RNA provided important insights into HIV-1 pathogenesis and accelerated the development of effective treatments. Co-investigator Alan Perelson used frequent plasma HIV-1 RNA measurements to demonstrate a biphasic decay in viremia following the initiation of combination antiretroviral therapy (ART). Following a very rapid initial decay in the first days few days of treatment, viremia falls more slowly over the new few weeks. The half-lives of these two phases of decay of viremia (termed here 1st and 2nd phase) are 1 day and 14 days, respectively. Fundamental principles of viral dynamics2-4 developed by Dr. Perelson suggest that the biphasic decay must reflect the presence of two distinct populations of virus producing cells with corresponding decay rates 1 day and 14 days. However, this prediction has yet to be verified. Concomitant measurement of changes in infected cell frequencies following ART initiation has been complicated by several factors including the presence of large numbers of defective proviruses. The recent development of digital droplet PCR assays for intact proviruses has allowed us to make such measurements in persons living with HIV-1 (PLWH) who are initiating ART and in SIV-infected macaques. In this proposal, we focus on the 2nd phase of decay of viremia which continues for several weeks after the very rapid 1st phase decay has eliminated most productively infected cells. Our fundamental hypothesis is that the 2nd phase decay represents a selection process which determines which cells will enter the stable latent reservoir. Only cells that survive this phase of decay may be able to downregulate HIV-1 gene expression and enter the stable latent reservoir, which we have shown has half-life measured in years (3.7 years). Therefore, we will analyze 2nd phase decay to develop novel insights into the composition and dynamics of the latent reservoir that may suggest new strategies for curing HIV-1 infection.