ABSTRACT: The combinational antiretroviral therapy is effective in suppressing HIV-1 replication. However, latent HIV reservoirs cannot be cleared by such antiretroviral therapy, as viral rebound develops rapidly after the treatment is interrupted in people living with HIV. The shock-and-kill approach to eliminate HIV-1 reservoirs is to induce viral reactivation using latency reversal agents and trigger cell death through virus-mediated cytopathic effects or immune-mediated clearance. However, shock-and-kill by latency reversal agents has not been shown to successfully reduce the viral reservoirs in HIV-1 patients. It has been reported that latency reversal agents can up-regulate pro-survival autophagy and anti-apoptotic molecules that counteract cell death signaling. Inhibition of these pro-survival mechanisms can promote the killing of HIV-1-infected cells, and facilitate the killing of HIV-1 reservoir cells during vial re-activation. Experiments are proposed to test hypothesis that cellular mechanisms that maintain the long-term persistence of HIV-1 reservoirs are important for protecting the reservoir cells against cell death, and targeting these cellular mechanisms can sensitize HIV-1 reservoirs to cell death during viral reactivation: 1) To determine the mechanisms for the specific induction of cell death in HIV-1 reservoirs in response to viral reactivation. The mechanisms for the induction of apoptosis and alternative cell death pathways in latent HIV-infected T cells by latency reversal agents will be tested; 2) To delineate the mechanisms that confer the resistance to cell death in HIV-1 reservoirs upon viral reactivation; and 3) To test whether targeting pro-survival mechanisms sensitizes HIV-1 reservoirs cells to cell death during viral re-activation. The studies will reveal novel molecular pathways that could be targeted to sensitize HIV-1 reservoirs to cell death, and facilitate the development of an effective approach to clear HIV-1 reservoirs.