A major barrier to HIV eradication is maintenance of latently infected cells in people living with HIV (PWH). The Veteran population of PWH is nearly 2.5-fold greater versus non-Veteran individuals living in the United States, underscoring a major unmet need within the United States Veteran's population for safe, specific agents that can cure HIV and prevent or reverse associated co-morbidities. Chronic inflammation despite suppressive ART drives HIV persistence and co-morbidities, including cardiovascular disease, frailty, diabetes, and HIV- associated neurocognitive dysfunction (HAND). The Janus Kinase Signal Transducer and Activator of Signal Transduction (Jak-STAT) pathway is a major mechanism of elevated immune dysregulation, even during viral suppression. In viremic individuals, elevated pSTATs including pSTAT5 are associated with increased reservoir size, viral loads, and decreased CD4+ T cell counts, underscoring the direct link between the Jak-STAT pathway and the HIV-1 reservoir. Our team (Vincent Marconi (VAMC) William Tyor (VAMC) and Christina Gavegnano) has extensively studied the class of Jak 1/2 inhibitors (indication HIV-1), including a first-generation Jak 1/2 inhibitor ruxolitinib, and demonstrated in a recently completed multi-site Phase 2a ACTG-sponsored study (A5336;n=60) that ruxolitinib is safe, well-tolerated, and reduces key markers of immune activation associated with HIV-1 persistence (HLA-DR/CD38, sCD14, and cellular lifespan marker bcl-2). We also showed a reduction in the HIV-1 reservoir in individuals with higher baseline frequency of integrated HIV-1 DNA, demonstrating proof- of-concept that Jak 1/2 inhibition can reduce the reservoir in a clinical setting. Furthermore, we observed that ruxolitinib, in an in vitro model of HIV-1-infection in total memory CD4+ T cells, pushes differentiation of central memory cells (TCM) to a shorter lived phenotype (effector memory T cells-TEM), which could also induce HIV- 1 reservoir decay. Baricitinib is a second-generation Jak 1/2 inhibitor (FDA approved for rheumatoid arthritis and COVID-19), presenting a markedly improved safety profile versus ruxolitinib including approval for chronic long- term use (including children), once daily dosing and renal clearance (making drug-drug interactions with hepatically cleared agents unlikely; critical for add-on to ART). We have shown that baricitinib significantly reduces the HIV-1 reservoir in primary T cells and reverses HIV-1 persistence markers and inflammation (murine model). We also demonstrated that baricitinib confers substantial improvement of CD4/CD8 HIV-specific effector function, boosting natural immune function that may i) enhance reservoir decline and ii) block or prevent inflammatory driven co-morbidities in PWH. However, how baricitinib can confer reservoir reduction in ex vivo patient samples, and in a dynamic in vivo (murine) model of systemic infection, remains unclear. We will define the multi-functional action of ba...