Abstract: HIV causes a spectrum of neurologic deficits known as HIV-Associated Neurologic Disorders (HAND). HAND is a prominent co-morbid condition of HIV even in the era of Combined Anti-Retroviral Therapy and is expected to increase as the HIV+ population ages. Fundamental understanding of how HIV invades the brain and mechanisms that drive HAND are poorly understood. In this application we will focus on the role of CD4+ T cells and CD4dimCD8bright T cells in HIV neuroinvasion, persistence, and HAND. CD4dimCD8bright T cells are a unique subset of CD8+ T cells that co-express CD4 on their surface. They exhibit potent anti-viral responses in the periphery. Recently, we showed that migration of CD8+ T cells into the CNS in context of HIV gives rise to CD4dimCD8bright T cells, in a Wnt/-catenin signaling - dependent manner. Within the brain, CD4dimCD8bright T cells exhibit highly potent anti-HIV responses. The consequence of this response is controlling HIV on one hand but perhaps at the cost of inducing inflammation and injury in the brain. Based on our published and preliminary data, we hypothesize that because peripheral CD4dimCD8bright T cells are susceptible to HIV infection, they will contribute to HIV neuroinvasion (Aim 1), yet because they robustly express -catenin and its pro-survival target gene, Bcl-XL, infected CD4dimCD8bright T cells will persist in the CNS as a reservoir for HIV (Aim 2). Further, because CD4dimCD8bright mount potent anti-HIV responses and are hyper-activated, their frequency will correlate with lower HIV content in CNS but higher level of neuroinflamamtion and worse neurocognitive performance (Aim 3). We will use a combination of in vitro, small animal studies, and patient samples from the Southeast Asia Research Collaboration with the University of Hawaii (SEARCH) and the US Military HIV Research Program (USMHRP) to address this central hypothesis. Collectively our studies will establish a new understanding of HIV neuroinvasion, HIV neuro-persistence, and role of T cells in the neuro-immune axis mediating neuropathogenesis/HAND. This understanding can provide new approaches for therapeutic intervention to ameliorate and/or reduce HAND and will provide valuable insights into HIV persistence in the CNS.