PROJECT SUMMARY The global rate of HIV infection and number of AIDS related deaths have dramatically declined thanks to the expanding access to combination antiretroviral therapy (cART). However, current cART is only able to suppress acute replication of HIV but fails to eliminate it. HIV epidemic remains unsolved and new HIV infections still occur at a remarkable rate worldwide. Furthermore, HIV infection, even under control of cART, still persistently associates with the chronic immune activation that attributes to the significant increase of risk for inflammation- related diseases and the accelerated aging process. Identification of novel host-HIV interactions critical to HIV infection will not only improve our understanding of HIV infection courses, but also accelerate the finding of new strategies to develop antiretroviral agents perturbing host regulatory factors, which can efficiently eliminate HIV, leading to a HIV/AIDS cure. Following HIV infection, Nef is expressed as one of the earliest and most abundant viral proteins and important to establishment of HIV persistent infection. Our recent studies have identified that HIV Nef plays a role in enhancing SUMOylation of polo-like kinase 1 (PLK1) and leading to its nuclear accumulation. We provided the evidence that depletion or inhibition of PLK1 promotes cell death of HIV-infected CD4+ T cells and facilitates elimination of HIV reservoirs. In this proposal, we aim to investigate the Nef-PLK1 axis based on our hypothesis that PLK1 is Nef’s host effector that executes its key function to promote cell survival and immune escape, thus supporting HIV persistent infection. We will investigate the molecular insights for HIV Nef to activate PLK1 protein SUMOylation and its nuclear accumulation. We will also dissect the signaling transduction of PLK1 to promote survival and immune escape of HIV reservoir cells. Beyond the fundamental studies, we will test the potential of small-molecule inhibitors targeting PLK1 as the reagents for elimination HIV reservoirs. It is well acknowledged that simian immunodeficiency virus (SIV) infection of macaques closely resembles HIV infection of humans, which serves as the best available animal model for studying progression and pathogenesis of AIDS. We will determine whether the function of Nef-PLK1 axis is conserved in SIV infection. We will also evaluate whether PLK1 inhibition is potent to eliminate SIV reservoirs. In Aim 1, we will investigate HIV/SIV Nef’s role in controlling PLK1 protein modifications and functions. In Aim 2, we will determine PLK1’s role in promoting survival and immune escape of HIV/SIV reservoirs. In Aim 3, we will evaluate therapeutic potential of PLK1 inhibitors for eliminating HIV/SIV viral reservoirs ex vivo.