SUMMARY HIV infected patients have twice the risk of cardiovascular disease relative to the general population. The main drivers of cardiovascular events in patients with HIV infection are associated with chronic immune activation, systemic inflammation and endothelial dysfunction. The molecular pathways linking HIV-driven chronic T immune activation, vascular inflammation and increased risk of cardiovascular disease are largely unknown. In this proposal, we will investigate the underlying mechanisms driving vascular inflammation/damage during HIV infection by focusing in the function of angiogenic CD8 T cells (CD8 Tangs). Under physiological conditions, Tang cells play a role in endothelial repair by promoting differentiation and proliferation of endothelial progenitors at the site of vascular injury. The mechanisms involved in CD8 Tang cell subset differentiation and function are not well defined. We hypothesize that HIV infection drives immune activation of CD8 Tang cells and impairs their ability to promote vascular repair and, the chronic interference of this pathway contributes to vascular inflammation and/or risk. In this proposal we will: 1) Identify the molecular pathways involved in the differentiation and function of CD8 Tang cells and the role of PAR1 signaling in this pathway. 2) Identify the impact of HIV driven T cell immune activation in CD8 Tang cell differentiation and/or function and evaluate its relationship with cardiovascular risk/disease in patients with HIV infection. 3) Mechanistically, in a murine model of LCMV infection, we will evaluate the role memory (tissue resident and circulating) CD8 T cells to undergo CD8 Tang cell differentiation and determine the impact of PAR1 deficiency in vascular repair and cardiovascular disease progression. These studies will establish the mechanisms of CD8 Tang differentiation and function in health and HIV infection. In addition, these studies will identify new molecular targets to restore CD8 Tang function in patients. This research will have wide application in multiple inflammatory diseases in which systemic inflammation is associated with cardiovascular risk. .