The mission of the DARE Collaboratory is to harness the power of the adaptive immune system to reduce the size of the reservoir during antiretroviral therapy (ART) and to control any residual virus after ART is interrupted. Our overall hypothesis is that that durable remission of HIV infection will require a robust immune response that is persistent and functional. Moreover, these responses need to be in the right place at the right time. We propose four highly linked research foci aimed at reaching these goals. We will define the role of putative immune-privileged sanctuaries that enable SIV/HIV to persist during ART and use the monkey model to develop therapies to breach these sanctuaries (Initial Research Foci 1, IRF1). We will characterize the distribution on replication-competent virus in lymphoid tissues of ART-suppressed adults and develop PET imaging modalities to quantify this reservoir (IRF2). We will define the role of immune checkpoints (PD-1, others) and their blockade on T cell function in monkeys and people (IRF3). Finally, we will define the safety, immunogenicity, and anti-HIV effectiveness of a human CMV (HCMV) vectored HIV vaccine in HIV-infected adults on ART (IRF4). All four initial research foci are linked by their shared goal to understand how best to quantify, reduce, and control HIV in the human lymphoid system. We anticipate meeting the following milestones and deliverables: (1) definition of the replication-competent reservoir in lymphoid tissues from SIV- infected monkeys and HIV-infected humans on suppressive ART, (2) determination of whether B follicles serve as a immunologic sanctuary for infected CD4+ TFH and, if so, whether B follicular depletion reduces the size of the reservoir, (3) determination of the characteristics of virus-specific CD8+ T cell responses that have optimal activity for reservoir reduction and/or post-ART viral control, (4) determination if the tissue reservoir can be measured by radiolabeled tracers and PET scanning, (5) identification of the optimal combination of immune checkpoint blockers that enhance T-cell function and/or reverse HIV latency, (6) definition of the safety and immunogenicity of immune checkpoint blockers in treated SIV and HIV disease, (7) determination of the safety and immunogenicity of the HCMV/HIV vaccine in treated HIV disease, and (8) determination if B cell disruption and/or immune checkpoint blockade might be necessary for this vaccine (or other comparable interventions) to achieve reservoir reduction and/or durable remission. Our work will set the stage for a future proof-of-concept clinical trial of the HCMV/HIV vector in antiretroviral-treated individuals, either alone or in combination with B cell follicle disruption and/or immune checkpoint blockade.