PROJECT SUMMARY/ABSTRACT: As people with HIV (PWH) age, chronic comorbidities such as cerebrovascular disease and poorer cognition become more prevalent. There exist a disparity in the rates of cerebrovascular disease and dementia among PWH. Possible contributing factors include disproportionate prevalence of vascular risk factors such as hypertension, diabetes, dyslipidemia and smoking in PWH. Additionally, the socioeconomic context of PWH (that includes but is not limited to homophobia, structural racism and societal stigma) may translate in stressors that may contribute to poorer vascular health. In this proposal, we attempt to fill in the knowledge gap of how vascular risk factors and socioeconomic stressors may affect cerebrovascular disease and cognition in PWH. We propose that soluble blood biomarkers of endothelial activation such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and tumor necrosis factor alpha (TNFα), are key mediators of these relationships, and more importantly, they could be therapeutic targets. In aim 1, we hypothesize that uncontrolled vascular risk factors and socioeconomic stressors interact with HIV to relate to increased levels of blood biomarkers of endothelial activation compared to age-, sex-, and ethnicity-matched uninfected controls. In aim 2, we propose that disparities in HIV-related cerebrovascular disease compared to uninfected controls are mediated by increased levels of blood biomarkers of endothelial activation. In aim 3, we hypothesize that disparities in MRI-based neurodegeneration and cognition in PWH compared to matched uninfected controls are mediated by increased levels of blood biomarkers of endothelial activation and MRI- based cerebrovascular disease. To confirm the central role of endothelial activators over other inflammatory molecules, we will carry out confirmatory analyses using five models that include LASSO without interaction terms, Lasso with interaction terms, RF, XGBoost and Model Average. With the execution of these aims, we will produce rigorous scientific evidence supporting the unique physiopathology of HIV-related cerebrovascular disease and neurodegeneracion. Furthermore, by establishing endothelial activation as a key pathway in mediating HIV-related disparities in cerebrovascular disease and neurodegeneration, we will provide preliminary support to test whether modification of these inflammatory pathways (e.g. TNFα blockade) may prove beneficial in PWH or in certain subgroups to be identified in this study.