The existence of a latent reservoir of HIV-infected cells constitutes the major impediment towards viral eradication. The HIV latent reservoir is small in number, but extremely long-lived. Latent infection is associated with undetectable levels of viral gene expression and appears to be non-cytopathic. The current thinking in the field is that a combination of hypothetical drugs that will reactivate latent viruses (Latency Reversing Agent or LRA), with present-day antiretroviral drugs, will be an effective approach toward viral eradication. Several clinical trials targeting the latent reservoir with LRAs have resulted in limited to no clinical effect on the size of the latent reservoir. To that end, strategies that can reactivate latent HIV and also enhance immune responses against HIV may overcome some of the disadvantages of current cure efforts. SUMOylation has been shown to negatively regulate the transcriptional activity of several STAT proteins. Importantly, STAT function is required for the proper mounting of an immune response. Our preliminary data suggest that SUMOylation control the activity of several STATs in human primary cells and downregulates immune responses. Based on these results, we propose that targeting SUMOylation of STAT proteins may open a novel opportunity to enhance anti-HIV immune responses and increase the efficacy of “shock-and-kill” strategies. In Aim 1, we plan to characterize the role of STAT SUMOylation in the biology of CD8T cells. Our preliminary data demonstrates that inhibition of STAT SUMOylation enhances both CD8T cell expansion and cytolytic function of polyclonally activated CD8T cells. We will address whether SUMOylation of STATs also control expansion and cytolytic function of HIV-specific CD8 T cells. Furthermore, we will investigate at the molecular level the mechanisms that enhance cytolytic function. In Aim 2, we intend to characterize the role of STAT SUMOylation in NK cell function. STATs have been shown to be important in NK function and our preliminary data shows that inhibiting STAT SUMOylation enhances NK proliferation and cytolytic activity. We plan to further evaluate the role of STAT SUMOylation in NK killing and in particular antibody-dependent cell- mediated cytotoxicity (ADCC) against HIV. Our preliminary data suggests that IL-15 controls CXCR5 expression, a chemokine receptor required for migration into B-cell follicles. Because IL-15 activates STATs, we will explore at the molecular level how IL-15 induces CXCR5 expression and whether targeting STAT SUMOylation enhances IL-15-mediated migration of NK cells towards B-cell follicles. Finally, in Aim 3 we will explore whether targeting STAT SUMOylation may aid in the reduction of HIV reservoirs ex vivo. This aim will be directed to find combinations of clinically relevant cure strategies with STAT SUMOylation inhibitors that reduce replication competent virus ex vivo.