PROJECT SUMMARY/ABSTRACT CD4+ T cells are the major target for HIV-1 infection, and their loss is a hallmark of HIV-1 disease. However, follicular helper T (Tfh) cells, a distinct subset of CD4+ T cells that are specialized in helping B cells to form germinal centers (GCs) for generation of high-affinity class-switched antibodies, expand in patients chronically infected with HIV-1. The observed Tfh cell expansion is not due to a lower susceptibility of this cell type to HIV-1 infection, as Tfh cells have been identified as a major CD4+ T cell compartment for HIV-1 infection and replication. Why Tfh cells are more permissive of HIV-1 replication is unknown. Whether infected Tfh cells efficiently revert back to a resting memory state to become a major reservoir of HIV-1 latency is also unknown. We hypothesize that Tfh cells have weakened cell-intrinsic antiviral immunity, thereby rendering these cells more susceptible to HIV-1 replication. We also hypothesize that some infected Tfh cells survive and revert back to a resting memory state and become cellular reservoirs of HIV-1 latency. To pursue these hypotheses, we formed a research team consisting of four scientists with complementary expertise in cell-intrinsic immunity, Tfh cell development, HIV-1 pathogenesis, and therapy. We have Preliminary Data showing that (i) Tfh cells express significantly lower levels of cell-intrinsic anti-HIV-1 restricton factors including IFITM3 (interferon-induced transmembrane protein 3) and MX2 (myxovirus resistance 2) than other CD4+ T cell types, which may be attributed to the high constitutive expression of the transcriptional repressor BCL6 (B cell lymphoma 6) in Tfh cells, (ii) BCL6 controls development of memory CD4+ T cells, and (iii) BCL6 controls development of CXCR5+ Tfh cells in immunized mice. Based on these preliminary findings, we have three Specific Aims to determine: (1) whether Tfh cells have weakened cell-intrinsic anti-HIV-1 immunity (Aim 1), (2) the levels of IFITM3 and MX2 in Tfh versus non-Tfh CD4+ T cells from HIV-1 patients and their relationships with the frequency of latently- infected Tfh versus non-Tfh CD4+ T cells (Aim 2), and (3) whether BCL6 controls Tfh cell survival and whether abrogation of BCL6 function induces killing of the long-lived latently infected Tfh cells from HIV-1 patients (Aim 3). With the ultimate goal of defining and eliminating HIV-1 reservoirs in infected patients, we propose to take advantage of a large cohort of HIV-1 patients to identify and characterize cellular reservoirs in HIV-1 patients. Our results will provide insights into how HIV-1 latency is established and maintained, and may lead to new therapeutic interventions for a functional cure of HIV-1.