As the HIV/AIDS research field embarks on an endeavor to cure HIV-1 infection, insight into the reservoirs that sustain viral persistence in the face of suppressive antiretroviral therapy (ART) is essential. Most of the focus has been on characterization of proviruses and viral outgrowth assays (VOA) using circulating CD4+ T-cells that may have limited ability to inform on the nature of the reservoirs in tissues and more importantly, the origin of the viruses that recrudesce upon ART interruption. Furthermore, these approaches do not reveal the potential contribution of non-CD4+ T-cells, such as tissue macrophages, to viral persistence and rebound. The timing and composition of rebounding viremia is likely to reflect the nature of the reservoir from which it originated and the quality of host antiviral immunity levied against it. Project 3 will assess viral reservoir activity prior to treatment interruption, as well as the composition of rebounding viremia, to gain insight into the virologic mechanisms whereby host antiviral immunity impacts viral rebound activity. Project 1 will provide longitudinal samples from completed and planned human therapeutic vaccine trials (BCN ATI, RISVAC03, BCN02 and AELIX003). The SIV macaque model (Project 2) will provide longitudinally sampled blood and tissues from ART-suppressed, RhCMVd10/SIV-vaccinated macaques after treatment interruption. Crucially, both projects allow the earliest sampling of rebounding viremia, which is most likely to reflect its origins in the reservoirs that persist under ART suppression. We hypothesize that immune responses in macaques elicited by RhCMVd10/SIV vaccination and in humans by a viral load ?data-informed? vaccine, impact viral reservoir activity and that this is manifest by an impact on time to viral rebound as well as activity and composition of the viral reservoir. To pursue this hypothesis, we propose the following specific aims: The objectives are to (i) evaluate the effect of therapeutic vaccination on viral reservoir activity, (ii) assess the effect of therapeutic vaccination on rebounding virus composition, and (iii) determine whether macrophage- tropic viruses present in rebounding viremia have a macrophage origin.
