PROJECT SUMMARY/ABSTRACT Despite the success of standard antiretroviral therapy (ART), the need for an HIV cure remains compelling, both to improve the lives of PWH and to bring about the end of the pandemic. Strategies for an HIV cure fall under two categories: those that seek ART-free ‘remission’, and those targeting a classical cure or ‘eradication’. While precedents exist for both scenarios, the latter have only been achieved with bone marrow transplantation. In contrast, although naturally occurring immune-mediated control of HIV (remission) is relatively rare, many such cases have been described. Our proposed “Martin Delaney Collaboratory for HIV Cure Research” program is entitled “REACH” - Research Enterprise to Advance a Cure for HIV. The central theme of REACH is that cellular immune responses (NK and T-cells), combined with next generation virus-neutralizing biologics, can be harnessed to achieve durable remission and eradication of HIV reservoirs. The proposed research focuses on closing gaps in our understanding of the fundamentals of the system that we are trying to perturb, i.e.: the HIV reservoir in relation to cellular immunity, as the means to achieve real progress towards effective and viable HIV cure strategies. Our approach centers around three research foci, which emphasize back to basics science, but connect this with discovery to translational pipelines directed towards both remission and eradication. The proposed objectives, broadly defined, aim to: (1) redefine the three-way relationship between the persistent HIV reservoir, CD8+ T-cells, and rebound virus at the levels of: single cells, individuals, and diverse populations, (2) harness conventional and unconventional (bNAb-induced) CD8+ T-cells responses, in combination with bNAbs and ‘next generation’ biologics, to achieve durable control of HIV replication, and (3) develop a discovery-to- translation pipeline to overcome multiple barriers to the eradication of HIV reservoirs by CTL/NK cells. These studies will be rooted in a strong basic science program that will contextualize results with novel insights into barriers to immune-mediated reservoir elimination, including the role of the proviral integration site and of viral and host factors influencing immune susceptibility. Our program prioritizes the study of diverse populations, including African populations infected with non-B subtype virus, and women – both to advance towards a cure for all, and to benefit from diverse perspectives as a source of fundamental insights. These objectives will be realized by a group of accomplished investigators of diverse expertise and with strong collaborative histories, along with community and industry partners.

PROJECT NARRATIVE Despite the success of standard antiretroviral therapy, the need for an HIV cure remains compelling, both to improve the lives of people living with HIV and to bring about the end of the pandemic. The “REACH: Research Enterprise to Advance a Cure for HIV” Martin Delaney Collaboratory comprehensive scientific plan aims to uncover mechanisms driving HIV persistence, including intrinsic resistance to cellular-mediated killing, to guide the development of novel combination approaches that can harness cellular immune responses to achieve durable remission and eradication of HIV reservoirs.