SUMMARY This project will leverage emerging knowledge about the role of immunometabolism in the pathophysiology of depression in people with HIV to generate hypotheses about potential future treatments. Depression in PWH is characterized by features that differentiate it from depression in people without HIV (PWoH). The first is the predominance of anhedonia - inability to gain enjoyment from activities. The second is a higher prevalence of depression that is resistant to treatment with standard antidepressant drugs in PWH versus PWoH. These clinical observations suggest not only that the underlying pathophysiology of depression is different between the two populations, but that different treatments are needed to successfully treat depression in PWH. Molecular studies of immunometabolism, defined as reciprocal interactions between immunity and metabolism that are dysregulated and linked to depression in PWH, support these distinctions. Based on our preliminary data and that in the literature, we propose to perform RNA-Seq transcriptomics, relating immunometabolic gene expression to protein and other biomarkers of immunometabolism, and to clinical depression as well as to cognitive processes impacted by depression. Our hypothesis-driven approach will focus on two interacting, co-regulated gene pathways central to depression and immunometabolism, the mammalian target of rapamycin (mTOR) and the NLRP3 inflammasome. We will study 80 newly recruited PWH and 40 age- matched PWoH. Given our early work suggesting that the relationship between immunometabolism and depression is sex-dependent, we aim for a 50/50 breakdown of men and premenopausal women in order to examine sex differences in these relationships. To optimize the spectrum of depressive symptom severity in our sample (e.g., avoid over-representation of individuals with minimal depressive symptoms), we will stratify with a 50/50 breakdown above and below the previously established Beck Depression Inventory-II cut-score for clinically-significant depressive symptoms (≥16). Since clinical studies cannot rigorously establish mechanistic relationships, we will study in parallel the roles of mTOR and NLRP3 inflammasome signaling in depression-like behaviors in a mouse model of HIV infection, EcoHIV, which expresses seven of nine key human HIV proteins. These pathways will be dissected using mTOR and NLRP3 inhibitors. Also, in these animals we will characterize immunometabolic markers in brain tissue, presumably the substrate of depression.