Project Summary/Abstract This is a resubmission application for a Mentored Research Scientist Development Award (K01) to support the career development of Dr. Stephanie Matt to facilitate her transition to an independent academic investigator in the HIV and neuroimmunology research fields. An intense and comprehensive mentoring and research plan has been developed to use high-throughput techniques to assess antidepressant-mediated HIV viral dynamics and inflammatory signaling in human myeloid and co-culture models. Dr. Matt’s training will be supported by a firm institutional commitment to her career development and a strong mentoring team of leaders in the HIV and psychoneuroimmunology research fields, each providing strategic guidance in both the development of this proposal and mentoring as her career progresses. The proposed research plan is a natural extension of the recent studies Dr. Matt has been conducting in her mentor Dr. Peter Gaskill’s laboratory but is distinguished by examination of HIV infection and inflammation in clinical cohorts, biostatistical analyses, as well as neuronal profiling. Neurological complications of HIV infection (neuroHIV) remain prevalent even with antiretroviral therapy (ART). Depression is one of these increasingly common complications that can substantively worsen HIV disease progression. Myeloid cells such as macrophages and microglia are primary HIV targets that can serve as viral reservoirs and drive HIV neuropathogenesis, but their activation also mediates depression-associated inflammation. Inflammatory links between HIV, depression, and the drugs used to treat them are not well understood. However, HIV, depression, and antidepressants act on receptors and transporters that alter neurotransmission, and neurotransmitter receptor activity on immune cells can influence inflammatory signaling and HIV infection. This suggests that changes in neurotransmitter levels by antidepressants could affect the size of myeloid HIV reservoirs, exacerbating neuroHIV and influencing the progression of depression and treatment resistance. Thus, the overarching hypothesis of this proposal is that specific antidepressants can activate both CNS and peripheral myeloid cells that critically contribute to inflammation and HIV persistence. This proposal will test this hypothesis using a multifaceted approach to evaluate the effects of in vivo antidepressants and ART on viral dynamics and inflammation in myeloid cells in association with cognitive function in depressed people living with HIV (Aim 1), effects of antidepressants regulating discrete viral dynamics in HIV-infected, ART-treated iPSC CNS and peripheral myeloid populations (Aim 2), and how antidepressants influence viral dynamics and neuronal function in co-cultures of HIV-infected, ART-treated microglia and distinct neuronal subtypes (Aim 3). These studies will significantly advance our understanding of the cellular mechanisms underlying the role of antidepressants in H...