PROJECT SUMMARY Despite the success of antiretroviral therapy (ART), people living with HIV-1 require life-long treatment due to viral persistence in long-lived cellular reservoirs, and experience a chronic state of immune activation and exhaustion that significantly contributes to the risk of cardiovascular disease and other life-threatening complications. The inability to address these clinically relevant shortcomings of ART represents a critical knowledge gap in the management of HIV-1 infection. Intensive efforts to perturb the latent reservoir via pharmacologic latency reversal or immune-based therapies targeting latently infected cells have not produced positive results to date. Similarly, attempts to directly address the chronic immune activation observed in chronic, treated HIV-1 infection have shown modest returns. The reservoir persists through cellular proliferation, though little effort has been made to evaluate the role of anti-proliferatives in reducing reservoir size. We and others have demonstrated the anti-proliferative and anti-HIV-1 effects of the FDA-approved drug and tyrosine kinase inhibitor dasatinib. While dasatinib has never been trialed for this indication, it was recently shown in a pilot clinical trial to act as a ‘senolytic,’ or a drug that can target cells responsible for the chronic inflammation associated with aging and aging-related conditions. The overall aim of this proposal is to plan a pilot clinical trial administering dasatinib to individuals living with treated HIV-1 infection to evaluate its ability to reduce the size of the HIV-1 reservoir and ameliorate the chronic immune activation that contributes to CVD risk in this population. The importance of developing strategies to address HIV-1 persistence, immunosenescence and serious pathophysiologic consequences including cardiovascular disease in treated HIV-1 infection are underscored by the chronologic aging of the HIV-1 infected population in the United States. The proposed pilot trial testing the anti-proliferative and senolytic properties of dasatinib in treated HIV-1 infection will have therapeutic implications for HIV-1 infection and a multitude of aging-related disease states including CVD.