PROJECT SUMMARY – THERAPEUTIC CORE The multiple CNS comorbidities present in HIV-infected individuals necessitate a more holistic approach in advancing new HIV neurotherapeutics. In line with these challenges, the JHU Center for the Advancement of HIV Neurotherapeutics (JHU CAHN) will evolve into a comprehensive research center targeting all aspects of CNS complications associated with PWH. The main objective of the Therapeutic Core is to serve as a dedicated drug discovery unit and to develop new therapeutics by working closely with other JHU CAHN cores as well as reaching out to investigators both in and outside the field of NeuroHIV including those affiliated with other NIMH NeuroHIV centers and the industrial sector. This ambitious goal will be enabled by a highly experienced drug discovery staff overseeing four key functions established within the Therapeutic Core, namely, medicinal chemistry, assay development/screening, drug metabolism and pharmacokinetics, and animal pharmacology/toxicology. The collective drug discovery-related resources will be directed toward investigators involved in NeuroHIV translational research, with a focus on early-stage investigators, under- represented minorities, and investigators new to HIV. The multidisciplinary structure tailored to drug discovery research also allows the core to provide a wide range of drug discovery training and educational opportunities (e.g., internships, fellowships, post-baccalaureate and graduate training, drug discovery and translational courses). Furthermore, the Therapeutic Core is uniquely positioned to promote awareness of HIV-related CNS complications among the industry sector by taking advantage of core’s extensive network built over years through multiple academic-biopharma partnerships. Working closely with the centers’ Biomarker, Clinical, and Developmental cores, the Therapeutic Core is poised to seize this opportunity by executing the following three Specific Aims: (Objective 1) Establish a drug discovery platform to develop novel therapeutics for CNS complications in PWH; (Objective 2) Evaluate drugs from Objective 1 for effect on neurobehavioral phenotypes in murine models of HIV; (Objective 3) Provide drug discovery education and services to the academic community. Engage with biopharma to investigate novel therapeutics for HIV comorbidities.