Project Summary Persons with HIV (PWH) have an approximate 2-fold higher risk of cardiovascular disease (CVD) compared to HIV-negative individuals, which is not explained by traditional risk factors and persists despite effective antiretroviral therapy. Some evidence suggests that cytomegalovirus (CMV), an almost universal co-infection in many subgroups of PWH, may be linked to increased CVD risk. However, CMV seropositivity alone (i.e., the presence of anti-CMV antibodies) has been insufficient as a predictor of CVD, potentially due to the greater importance of cellular immunity in the CMV-CVD pathway. Cardiovascular events are the leading cause of death in PWH and although CMV is thought to be important, its specific contribution to CVD in PWH is unclear. Current knowledge on the contribution of CMV to CVD is limited in several ways: 1) Few human studies have assessed peripheral blood circulating anti-CMV T cells and prevalent atherosclerosis. 2) There is a paucity of data on whether CMV-specific T cells are present within human atherosclerotic plaque. 3) At present there is not a reliable animal model to investigate the infiltration of virus-specific T cells into plaque. We have shown that CD4+ T cells co-expressing the surface markers CX3CR1, GPR56 and CD57 (i.e. `C-G-C') are largely CMV- specific. We also showed that C-G-C+ CD4+ T cells are increased in the blood of PWH with metabolic disease and subclinical atherosclerosis. As the chemokine receptor CX3CR1 is highly expressed on CMV-specific T cells and traffics cells to activated endothelium, we hypothesize that inflated anti-CMV C-G-C+ CD4+ T cells recruited to inflamed endothelium via CX3CR1 are a major driver of subclinical atherosclerosis in PWH. I am a physician scientist skilled in immunology and microbial pathogenesis with training in infectious diseases. My tailored career development plan will advance my skills through experiential, didactic and professional training in: (1) tissue immunology; (2) atherosclerosis-pathogenesis; (3) clinical and translational research; (4) human-mouse chimera models; and (5) responsible conduct of research. With a transdisciplinary mentoring panel with expertise in HIV clinical research, epidemiology, single cell immunology, CVD, and atherosclerosis, I will accomplish the following aims. In Aim 1, we will test the hypothesis that peripheral C-G-C+ CD4+ T cells are CMV-specific and associated with subclinical atherosclerosis in PWH. In Aim 2, we will test the hypothesis that plaque-infiltrating C-G-C+ CD4+ T cells are CMV-specific. In Aim 3, we will use a mouse model to test the hypothesis that recruitment of circulating CMV-specific C-G-C+ CD4+ T cells to inflamed atheroma is CX3CR1-dependent. Completion of these specific aims will increase our understanding of whether CMV has an important role in CVD in PWH. With the completion of my career development plan, I will gain expertise in clinical and translational research, vascular biology, and cutting...