PROJECT SUMMARY: As people with HIV (PWH) age, chronic comorbidities such as cerebrovascular disease and poorer cognition become more prevalent. There is a difference in the rates of cerebrovascular disease and dementia among PWH compared with uninfected individuals. 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 may translate into stressors that contribute to poorer vascular health. In this proposal, we attempt to fill in the knowledge gap of how vascular risk factors and socioeconomic context, like income, stress, and health literacy, 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, that they could be therapeutic targets. In aim 1, we hypothesize that uncontrolled vascular risk factors and socioeconomic context 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 differences 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. With the execution of these aims, we will produce rigorous scientific evidence supporting the unique physiopathology of HIV-related cerebrovascular disease and neurodegeneration. Furthermore, by establishing endothelial activation as a key pathway in mediating HIV-related cerebrovascular disease and neurodegeneration, we will lay the groundwork to test whether modification of these inflammatory pathways may prove beneficial in PWH.