Project Abstract The proposal in this application will utilize systems biology approaches to get at the underlying pathogenesis of mood disorders including major depressive disorder (MDD), bipolar disorder (BD), MDD combined with generalized anxiety disorder (GAD) in people with HIV (PWH) virologically-suppressed on antiretroviral therapy (ART). The overreaching goals are 1) to identify both common and mood disorder-specific gene expression signatures in PWH on ART that correlate with the presence and severity of symptoms according to computerized adaptive testing for mental health using comparative whole blood transcriptomic analysis while carefully considering concurrent GAD, and/or prior childhood trauma; 2) to validate and mechanistically dissect transcriptomic and metabolomic signatures of MDD, BD, and MDD with GAD in PWH on ART utilizing targeted flow cytometry and metabolomics to validate differentially enriched genes and pathways; and 3) importantly, to find therapeutics that could potentially reverse dysregulated pathways by applying a novel algorithm, drug perturbation gene set enrichment analysis, to identify phenotypically-relevant, FDA-approved and repurposeable therapeutics as potential novel treatment options for PWH with mood disorders. To complete the experiments and answer these complex questions, an expert team has been assembled with the plan to recruit a cohort of PWH virologically suppressed on ART in five groups: 1) MDD, 2) BD, 3) MDD and GAD, 4) GAD, and 5) no mental health diagnoses. This cohort will be followed for 24 weeks and data will be collected for transcriptomic, metabolomic and flow cytometric responses to the presence and severity of mood disorder symptoms.