PROJECT SUMMARY/ABSTRACT Despite major advances in combination antiretroviral therapy (ART), adults living with HIV infection continue to suffer from high rates of morbidities associated with chronic immune activation, including neurocognitive impairment. Indeed, the prevalence of neurocognitive disorders in adults with HIV remains unchanged in the ART era: an estimated 50% of adults with virologically suppressed HIV have some form of neurocognitive impairment. Understanding the cellular basis for persistent CNS immune activation is thus critical for reducing neurological morbidities in the growing population of adults with HIV on treatment. Studies to date have focused on CSF biomarkers or CSF immune cell flow cytometry, but these studies are limited by the need to pre-specify markers of interest, thus missing the opportunity to identify de novo cell populations that may drive CNS immune activation and downstream neuronal damage, including rare myeloid subsets. The candidate has developed a reliable pipeline to profile single cerebrospinal fluid (CSF) immune cells at the transcriptional level, and has successfully used this technique to identify a rare cellular subset in CSF that presents a gene expression pattern consistent with disease-associated microglia. The research proposed here will utilize these state of the art methods to analyze CSF and blood from adult volunteers with and without HIV disease, to characterize novel or rare cell populations in the CNS during treated, suppressed HIV. Defining CNS immune activation in exquisite detail, including cellular populations that distinguish HIV infection during ART, has the potential to provide critical targets for therapeutic intervention for residual neurologic impairment during HIV treatment. The principal investigator is a physician scientist, with specialized training in Neuroinfectious disease and a PhD in Neurogenetics. Her career goal is to become an independent investigator studying neurological sequelae of infectious diseases, with a special focus on neurological effects of HIV infection. The proposed K23 training plan will provide the candidate with mentorship and coursework to build specific expertise necessary to execute the proposed project and become independent in her field, including expertise in: 1. Immunology and Neuro-infectious diseases 2. “Big data” genomics and associated computational analysis, and 3. Skills necessary to head an independent, patient-oriented research program. To achieve these goals, Dr. Farhadian has assembled a primary mentoring team consisting of experts in Neuro-HIV, Neuroimmunology, and Bioinformatics.