PROJECT SUMMARY/ABSTRACT: NeuroVirology and Biology (NVB) The NeuroVirology and Biology (NVB) core will focus on four major themes underlying NeuroHIV, in line with the HIV Neurobehavioral Research Center (HNRC) priorities and the OAR scientific agenda: 1) the impact of viral epigenetics on HIV persistence in the central nervous system (CNS), 2) latent or clinically asymptomatic co- infections, 3) mitochondrial biogenesis, 4) brain macrophage and astroglial response to systemic mediators of inflammation and current antiretroviral therapy (ART). The NVB core will continue to enhance the HNRC’s transdisciplinary focus through close collaborations with the NeuroBehavioral and Psychiatry, NeuroMedical, Microbiome and Developmental Cores, and utilizing laboratory and analytic techniques specific to CNS-derived viral and cellular populations in the setting of neurocognitive and other neurobehavioral consequences. The NVB Core is structured in two complementary units: NeuroVirology Unit and NeuroBiology Unit. These units will be an integral and indispensable part of the HNRC, and will provide invaluable knowledge and technologies to enhance research productivity and scientific input to meet the Center’s overall goals and objectives. · The NeuroVirology Unit will provide expertise and a broad range of validated and clinically relevant laboratory-based assays with the highest quality and most convenience possible. This Unit has a research focus on HIV persistence within the CNS and will continue to offer assays to characterize the HIV reservoir in the brain and in myeloid cells, with a new focus on proviral epigenetics. It will offer cutting-edge sequencing methods to characterize the epigenetic landscape of the HIV provirus from clinical samples. This Unit will characterize viral (genotypic and phenotypic), and other factors (co-infections, inflammation, mitochondrial damage) associated with neurocognitive and other neurobehavioral consequences, such as depression. · The NeuroBiology Unit will perform state-of-the-art neurobiology and neuropathology analyses of human brain tissues and in vitro experimental systems, that allow NeuroHIV investigators to understand the cellular mechanisms associated with mood and neurocognitive disorders. It will analyze the potential neurotoxic effects of current ART regimens on specific neuroglial cell populations. The NeuroBiology Unit will investigate the effect of ART and HIV on mitochondrial biogenesis in brains, and in vitro in cultures exposed to ART. In support of the Center’s expanded focus on depression and depression related factors, this unit will study the impact of anti-depressant medication on neuronal homeostasis, focusing on markers of autophagy and associated gatekeepers, e.g. brain immunophilins. The NeuroBiology Unit will incorporate the biomarker findings from the NeuroMedical Core in the research plans using banked specimens from the CNTN/NNTC. Finally, the NVB core will continue to prov...