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 psychiatric symptoms in future R
grant proposals and facilitate my independent research program focused on the role of monocytes in
inflammation-associated behavioral symptoms in PWH and other medical or psychiatric illnesses.
