PROJECT SUMMARY/ABSTRACT Overall, the world population is aging and in the era of anti-retroviral therapy (ART) people living with HIV (PLWH) live longer. ART has converted HIV infection into a survivable chronic infection; however, comorbidities are a mounting clinical reality, likely related to accelerated immunosenescence. It is well documented that HIV infection leads to accelerated aging, and HIV-1 chronic infection is considered a good model for studying immunosenescence. The impact of aging on increased susceptibility to infections and reduced responsiveness to vaccines is a well-known clinical problem. Antibodies are one of the first and most important responses against pathogens and the reason for this dampened immune response with aging may be due to age-related reduced humoral immunity (B cell immunosenescence). Humoral immunity has been understudied in humans, particularly in lymphoid tissue, due to the difficulty of sample availability. It is not clear how accurately changes observed in blood reflect immunosenescence processes in tissues, especially the gastrointestinal mucosa which contains most of the body’s lymphocytes (~60%) and it is a region of high antigen exposure. Therefore, gut-associated lymphoid tissue (GALT) represents a good model to study lymphoid tissue in humans that is highly exposed to antigen stimulation. A growing body of literature has begun to reveal the pathophysiological processes driving immune dysfunction of T cells, including work by our team, which has studied the human mucosal immune compartment. It is not well understood how aging depresses humoral immunity and there are little or no studies on humoral immunity in the mucosal immune compartment. Compared to blood, gut mucosa contains fewer naïve cells, more activated memory cell, and more antibody secreting cells, consistent with the high level of antigen exposure. Therefore, in this study, we propose to analyze the individual and combined impact of age and HIV-1 on immunosenescence of humoral immunity, especially in the highly immune active gastrointestinal tract, by quantifying B-cell immune aging in GALT and peripheral blood in PLWH, as a model of accelerated aging, and in people without HIV (PWOH). Our hypothesis is that natural aging and HIV-1-induced-accelerated aging diminishes the capacity of the immune system to produce efficient antibody responses in the periphery and GALT; this will be a result of inappropriate accumulation of memory-effector T-cells fueled by chronic persistent viral infections, causing ineffective follicular helper T-cells, inefficient recall of cytotoxic responses, and a generalized, persistent low-level inflammatory state. The Specific Aims to test this hypothesis are: Aim 1: To determine age-related B cell lymphocyte senescence in the GALT versus peripheral blood compartments of PWOH and PLWH ranging in age from 18 to ≥60-65 years. We will also study the functional aspects of B cells in terms of antibody production and B...