OVERALL PROJECT SUMMARY/ABSTRACT For over two decades, the NIMH P30 HIV Neurobehavioral Research Center (HNRC) has been a leader in the neuroHIV field, supporting research that has greatly advanced our understanding of the central nervous system (CNS) consequences of HIV disease, as well as their predictors, prevention, diagnosis, and treatment. In this renewal application, we propose to continue supporting innovative, basic/mechanistic, clinical, and translational studies of HIV, its treatment, and comorbidities. This will include studies of persistence (e.g., proviral epigenetics) and eradication of HIV in the CNS (“cure” agenda) and the role of gut microbiome alterations in HIV-associated CNS disorders. Depressive disorders have long been recognized to be highly prevalent among persons with HIV (PWH) and, especially when combined with cognitive impairment, may result in adverse consequences in many areas of public health concern, including poorer healthcare engagement, antiretroviral therapy effectiveness, social engagement, and life quality. Using both dimensional and diagnostic assessment approaches to depression and cognition, we aim to support research identifying and characterizing complex neurobehavioral phenotypes in PWH, determining their underlying biological mechanisms (e.g., inflammation, gut dysbiosis), and examining their effects on critical outcomes in PWH. These aims will be achieved by drawing on data and biospecimens from a registry of over 1200 well characterized PWH and HIV-uninfected participants, who have received comprehensive HNRC examinations during the last 5 years. During the proposed renewal period, we also will enrich the HNRC data and biospecimen resource by conducting 200 comprehensive assessments per year of registry participants who are identified on briefer semi-annual assessments as undergoing changes in neuromedical status, mood, cognition, or everyday functioning. The HNRC Participant Registry also will be refreshed with new participant enrollments. Together, these evaluations aim to determine the biological mechanisms underpinning neurobehavioral changes in PWH, as well as their clinical risk factors and consequences, with a view toward informing future interventions. This renewal builds on the track record of the HNRC as a national and international leader and a resource that facilitates research on pathogenesis, phenomenology, treatment, and prevention of neurobehavioral disturbances in PWH. To accomplish these goals, we propose four redesigned Scientific Cores (NeuroBehavioral and Psychiatry, NeuroMedical, Microbiome, and NeuroVirology and Biology) that will strongly support the HNRC aims and provide intellectual leadership and technical support. An Administrative Core will support and coordinate their activities, and a Developmental Core will support innovative pilot studies and coordinate training opportunities to help advance the careers of the next generation of neuroHIV scientists.