Project Summary Cardiovascular disease (CVD) remains the leading cause of mortality in women, with approximately one woman dying per minute in the US. Women living with HIV (WLHIV) are a particularly high-risk group of women with high CVD prevalence who have long been understudied in clinical research. As compared with uninfected women, WLHIV have a 2 to 4-fold increased CVD risk that persists later life and which is on par with men living with HIV. Additional research on sex-specific mechanisms of HIV-associated CVD will better inform the development of CVD prevention and treatment approaches clinically relevant to over 16 million women with HIV globally. Current CVD treatment approaches for PWH are lacking and have focused on applying cardiology guidelines from the general non-HIV population to PWH, however traditional risk assessments tend to underestimate CVD risk, possibly due to higher levels of chronic inflammation recognized in PWH, and pronounced in WLHIV. Initial work performed in the Hays lab demonstrated that nitric-oxide mediated coronary endothelial dysfunction, which contributes to atherosclerosis and predicts adverse cardiovascular events, is present at early ages in women and men with HIV compared to age-matched control participants without HIV. During the course of our initial work, we identified emerging risk markers in women and men with HIV such as abnormal fat distribution and associated inflammation, lipoprotein metabolism, and early menopause (in women) which may contribute to early impaired CEF. However, these early studies were cross-sectional in nature, and it is unclear how these important risk markers influence vascular health over time in women compared to men with HIV. The goal of the Hays lab over the next few years will be to: 1) better understand contributors and sex- specific pathways that underlie progression of heart disease in PWH with a focus on the role of ectopic fat deposition on long term vascular endothelial health 2) to evaluate and test novel risk markers (both targeted and untargeted markers using proteomics) for sex-specific CVD risk in PWH and 3) identify potential treatment targets that may be rapidly translated and tested in clinical trials in PWH. For the first two goals, we propose a longitudinal study with equal numbers of men and women with HIV across the lifespan to test the hypothesis that a hyperinflammatory milieu characterized by abnormal fat distribution, increased systemic inflammation and abnormal lipoprotein levels result in worsening CEF over time in PWH. The identification of important biologic drivers of increased CV risk in PWH is critical to define new therapeutic approaches. We will also study glucagon-like peptide-1 receptor agonists (GLP-1RA) that may reduce ectopic fat and slow the progression of CVD in PWH. My research program will address significant knowledge gaps regarding sex-specific factors that affect vascular health in PWH and provide data to design future interve...