Project Abstract Antiretroviral therapeutic (ART) drugs have greatly increased the lifespan of people living with HIV-1/AIDS. However, these same people experience ~50% prevalence rates of HIV-1 associated neurocognitive disorders (HAND). Increasingly noted in HIV-1 infected individuals are clinical manifestations and pathological features of Alzheimer’s disease (AD) including cognitive impairment, increased levels of amyloid beta protein (Aβ), increased levels of phosphorylated tau protein (p-tau), and synaptic dysfunction. Not only is the pathogenesis of HAND unclear, but relatively little is known about the extent to which HIV-1, HIV-1 proteins, and/or ART drugs act as “aging and AD accelerators”. The objective for this Alzheimer’s-focused Administrative Supplement (NOT-AG-20-008) is to determine the extent to which and mechanisms by which HIV-1 Tat protein contributes to the development of AD-like pathology. Our central hypothesis is that HIV-1 Tat interacts with the SLC38A9 arginine sensor in endolysosomes, promotes the disassembly of the v-ATPase proton pump in endolysosomes, and causes AD-like pathology. Guided by our preliminary findings, this novel hypothesis will be tested by pursuing two specific aims. (1) Determine the extent to which and mechanisms by which Tat causes v-ATPase disassembly. (2) Determine the extent to which and mechanisms by which Tat induced v- ATPase disassembly causes AD-like pathology in primary cultured neurons. The proposed studies here will explore novel mechanisms whereby Tat induces disassembly of v-ATPase via a lysosome arginine sensor, and we will focus on how Tat-induced disassembly of v-ATPase contributes to AD-like pathogenesis. Further, we expect that promoting the assembly of v-ATPase will attenuate Tat-induced AD-like pathology. The proposed studies are within the scope of the awarded R01 (MH119000-01) that is focused not on AD or its related dementias, but rather an involvement of v-ATPase in Tat endolysosome escape and HAND. Results of the proposed studies will not only lead to novel mechanistic insights into the co-pathogenesis of HAND and AD, but also provide rationale for developing endolysosome-acidifying agents as novel therapeutic strategies.