PROJECT SUMMARY Major barriers to HIV cure include functional impairment of virus-specific CD8+ T cells and evasion of immune detection by a reservoir of latently infected CD4+ T cells, both of which persist during antiretroviral therapy (ART). Critical knowledge gaps in our understanding of the biology regulating both processes limit development of effective immune therapies to obviate the need for lifelong adherence to ART in persons with HIV (PWH). The long-term goal is to inform development of such therapies by elucidating molecular mechanisms underpinning HIV-specific T cell dysfunction and viral persistence. The objective of the proposed research is to identify and modulate molecular pathways that govern T cell antigen sensitivity in PWH. The rationale is that this information will guide innovative strategies to combat HIV persistence. Based upon preliminary data identifying a previously unrecognized T cell activation deficit, distinct from exhaustion, which underlies failure to durably control HIV infection and an understudied role for monocyte–T cell interactions in altering antigen sensitivity, the central hypothesis that modulation of T cell activation thresholds will facilitate immune clearance of HIV-infected cells from persistent viral reservoirs will be examined in three research areas. The first aims to identify and perturb regulatory mechanisms governing antigen-refractory HIV-specific CD8+ T cells, including their maintenance by epigenetic control of inhibitory genes and/or cell surface receptors. The second research area aims to define contributions of HIV-infected antigen-refractory CD4+ T cells to viral persistence, including characterization of their proviral landscapes and their capacity for latency reversal. The third research area aims to harness monocyte-mediated modulation of T cell activation thresholds for HIV elimination by defining cell-surface interactions between monocytes and both CD4+ and CD8+ T cells that modulate antigen sensitivity and then examining their ability to improve HIV latency reversal and cytolytic viral clearance. The approach is innovative because it examines novel concepts, establishes new collaborations, and applies high-resolution techniques to investigate a newly identified dysfunctional T cell state using primary clinical specimens from PWH. The proposed research is significant because its successful completion will reveal fundamental human T cell immunobiology that can be exploited to enable the recognition and elimination of persistent HIV reservoirs by autologous cellular immune responses.