PROJECT SUMMARY The goal of this K01 is to determine the role of monocytes in HIV-related depressive symptoms with a focus on immunometabolic mechanisms that may fuel monocyte activation and trafficking to the brain and serve as therapeutic targets. Simultaneously, this mentored clinical research experience will provide me with essential training in immunometabolism, clinical HIV research, and translational approaches to drug design and discovery to launch my independent career. To achieve these goals, I will integrate clinical studies with innovative in vitro platforms including a “human blood-brain barrier (BBB)-on-a-chip” and immune cell metabolic assessments in people with HIV (PWH) treated with the anti-inflammatory drug baricitinib. Despite anti-retroviral therapy, persistent HIV-associated inflammation is thought to impair reward circuits in the brain and perpetuate motivational deficits like anhedonia and apathy in PWH. Activation of circulating monocytes is a key driver of inflammation, and transmigration of monocytes across the BBB contributes to inflammation in the brains of PWH. The mechanisms of monocyte activation and trafficking to the brain are not fully understood but may involve metabolic reprogramming in monocytes. Activated myeloid cells undergo a metabolic shift to glycolysis that sustains pro-inflammatory processes such as cytokine release and cellular migration. In patients with depression and high inflammation, our preliminary data show relationships between anhedonia and circulating monocytes characterized by glycolysis and markers related to trafficking to the brain. In pre-clinical models of depression, monocyte trafficking to reward-related brain regions is required for development of anhedonic behavior, whereas in PWH, activation and BBB transmigration of patient monocytes in vitro are associated with neurocognitive impairments. Thus, glycolytically activated monocytes may traffic to and/or across the BBB to promote anhedonia, and determining the role of monocyte metabolism and migration in inflammation and its impact on the brain is a critical next step to understand and treat motivational deficits in PWH. Leveraging patients, data, and resources from two ongoing parent studies examining inflammation, brain circuits, and neuropsychiatric outcomes in PWH before and after baricitinib, an anti-inflammatory drug shown to reduce HIV-related neuroinflammation and cognitive deficits in a pre-clinical model, I will examine monocyte glycolysis and BBB transmigration as pathways to peripheral and CNS inflammation, reward circuit deficits, and anhedonia in PWH. As part of this proposal, I will receive focused mentorship in research and career development from a team of recognized leaders in psychiatry, metabolism, HIV pathophysiology, and drug development. These studies will provide pilot data and innovative experimental platforms for testing novel strategies targeting monocyte metabolic and migratory pathways in PWH with psych...