Late Treatment Research Project (RP): Blood and Tissues Reservoirs

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PROJECT 2. LATE TREATMENT ABSTRACT: Blood and Tissues Reservoirs Most human studies have characterized circulating reservoirs and some non-blood HIV reservoirs using limited biological samples from otherwise healthy HIV-infected individuals, like genital sections, gut biopsies and cerebrospinal fluid, or autopsy specimens with little pre-mortem characterization. Therefore, our understanding of how HIV populates tissues throughout the body and how these populations are associated with each other- remains limited. Our proposed Revealing Reservoirs during Rebound (R3) program will take the next steps in finding a cure for HIV by understanding how HIV persists in and populates reservoirs throughout the body. Specifically, the Late Treatment Research Project (RP) will maximize data and samples collected from a `Last Gift' cohort of HIV-infected terminally-ill individuals. These altruistic individuals will provide: (i) detailed clinical, risk and socio-demographic information before their death; (ii) weekly blood collections while they are alive, before and after voluntarily stopping ART and, (iii) their entire bodies after they die. This cohort will allow us to characterize the HIV populations in blood before ART is stopped and during rebound viremia, and throughout the body after death. To complement studies proposed in the Early Treatment RP, this RP will determine: Aim 1: Virologic and immunologic quantities measured during ART that predict dynamics of viral rebound dynamics when ART is stopped (timing, size, slope); Aim 2: Dynamics of HIV variants populating CD4+ T cell subsets and in various anatomic tissues after ART interruption. Aim 3: Determine immunologic mechanisms associated with HIV persistence during ART and after ART interruption. By investigating HIV-infected individuals who started ART during chronic infection and thus have larger HIV reservoirs and more immune damage from HIV, the Late Treatment RP will complement the Early Treatment RP, which will investigate persons who started ART during acute and early infection, and thus have smaller HIV reservoirs and more intact immune systems. This RP will also create new knowledge about how HIV resides in circulating CD4+ T cells and in anatomic tissues, and these data will be analyzed in conjunction with data from the Early Treatment RP vianew analytical methods with the Quantitative Methods RP to more fully understand HIV dynamics throughout the body.