Summary - Overall To understand HIV-1 reservoir dynamics, we must understand how the reservoir is formed. The overall goal of this research program is to study dynamics of the latent reservoir through single cell analysis of the viral decay processes that determine the composition of the reservoir. Seminal studies by co-investigator Alan Perelson showed that following initiation of combination antiretroviral therapy (ART), plasma virus levels decay rapidly in a striking biphasic fashion. These studies established that in untreated people living with HIV-1 (PLWH), most of the virus in the blood is produced by infected cells that die or transition to a non-productive state of infection very rapidly. The half-lives of the two phases of decay are 0.7 days and 14 days. It is important to note that these decay processes occur continuously throughout untreated infection and are simply revealed when new infection events are blocked by ART. Thus, they are an essential feature of HIV-1 biology. Surprisingly, the identity and fate of the cells that decay with these kinetics have never been clearly defined. Coincident with the initial studies of HIV-1 dynamics by Perelson and colleagues, studies from the Siliciano lab established that HIV-1 could persist in a latent form in resting CD4+ T cells, and it rapidly became clear that the half-live of this latent reservoir was extremely long (3.7 yrs), long enough to preclude cure even with optimal ART. Using an SIV/macaque model, Dr. Dan Barouch showed that this reservoir is established very early in infection. A fundamental hypothesis of this research program is that the latent reservoir is composed of cells that survive the rapid decay processes that eliminate the vast majority of infected cells. We believe that insights into reservoir dynamics can be obtained through analysis of these decay processes. We will analyze these decay processes in coordinated studies in PLWH (Dr. Robert and Janet Siliciano, Project 1) and in SIV-infected macaques (Dr. Barouch, Project 2) with the help of Dr. Perelson and the Modeling Core.