PROJECT SUMMARY – CLINICAL CORE Over the past 15 years, the Johns Hopkins (JH) NIMH P30 Center focused on furthering discovery and application of novel therapeutics to address HIV-associated Cognitive Disorders, and successfully advanced NeuroHIV research globally. During this time, the Clinical Core has grown and maintained longitudinal participation of a well-characterized cohort of people with HIV (PWH) and matched HIV-uninfected individuals, and successfully disseminated richly phenotyped clinical and behavioral data, biospecimens, and analytical expertise to over 50 NIH-funded studies, including a 24 week Phase I/II pilot trial of intranasal insulin for the treatment of HIV-associated neurocognitive disorder. From these valuable human data, we gained crucial insights into the heterogeneity of central nervous system (CNS) system dysfunction that manifests as varied cognitive impairments as well as affective (mood including anhedonia, social withdrawal & anxiety) symptoms and somatic symptoms (sleep), along with divergent patterns in cognitive treatment response. We also learned that 24 weeks of intranasal insulin vs. placebo improved memory and attention in PWH. In response, our group was early to pivot toward a new model of innovation in therapeutic development, namely a personalized medicine approach developing and disseminating algorithmic, patient data-driven approaches to best select therapeutic targets and predict individual treatment response in PWH. In 2017, the Core moved toward mentoring rising leaders in big data harmonization and machine learning, broadening the clinical data collection to capture behavioral and self-report metrics relevant to mood and anxiety symptoms, integrating brain measurements, and incorporating assessments of genetic endowment, maladaptive behaviors, and life experience. Through this effort, the Clinical Core was among the first to capitalize on the NIMH Research Domain Criteria (RDoC) framework in the NeuroHIV field, an approach that will facilitate precision medicine approaches to treating neuropsychiatric complications in PWH. Over the next five years, the Clinical Core will collaborate with other JH Cores and those outside our Center to continue to innovate as a critical resource in the NeuroHIV field. Specifically, the Clinical Core will support projects in target discovery, therapeutic development, and clinical trials. In the context of this framework, we aim to: 1) Establish a resource to provide richly phenotyped clinical data, to support the study of critical pathways/circuits underlying CNS dysfunction, and inform therapeutic development and application in PWH, 2) Provide consulting services to the academic NeuroHIV community in terms of RDoC implementation, 3) Mentor the next generation of NeuroHIV scientists with integration of the RDoC framework, and 4) Engage and educate the community of PWH through multiple outreach programs.