PROJECT SUMMARY Neurocognitive impairment (NCI) affects up to 50% of persons living with HIV (PWH), including individuals with well-controlled infection. Biological sex is an important determinant of NCI among PWH. The strongest available evidence indicates that women with HIV have greater cognitive deficits globally than men with HIV and, most prominently, in learning, memory, and processing speed. Although women make up half of the world’s HIV population, few studies have focused on the mechanisms underlying sex differences in the prevalence and pathogenesis of NCI in PWH, despite the consequences that these differences could have on developing distinct therapeutic approaches to NCI for women and men. At least two pathways may differentially impact cognitive health in women and men with HIV, both through their association with cerebrovascular injury: (1) cardiovascular disease (CVD) risk factors and (2) immune activation and inflammation. Our central hypothesis is that NCI is more prevalent in women with HIV than in men with HIV due to greater burden and progression of cerebrovascular injury from increased susceptibility to the effects of CVD risk factors and immune activation. In Aim 1, we will determine if sex modifies the association of CVD risk factors and immune activation with cerebrovascular injury in PWH. In Aim 2, we will compare the burden and progression of cerebrovascular injury between women and men with HIV. In Aim 3, we will examine the extent to which cerebrovascular injury mediates the higher prevalence of NCI and decline in women with HIV and if sex modifies the association between cerebrovascular injury and NCI. To achieve our aims, we propose a prospective study that will leverage the research platform provided by the NIH-funded Multicenter AIDS Cohort Study (MACS)/Women’s Interagency HIV Study (WIHS) Combined Cohort Study (MWCCS). We will enroll 150 women (100 post-menopausal and 50 pre-menopausal women) and 100 age-matched men from the MWCCS to ensure the study is adequately powered to determine if sex modifies the associations between CVD risk factors, immune activation, cerebrovascular injury, and NCI. To the longitudinal neuropsychological data and stored blood specimens collected in the MWCCS study, we will add a comprehensive cerebrovascular imaging assessment, including of cerebral vasoreactivity, large artery, and small vessel disease, that will yield a complete profile of cerebrovascular injury. We will also measure immune activation and inflammatory markers that are associated with both cerebrovascular injury and NCI in PWH and have been shown to be higher in women compared with men. The findings of this study will provide new information on sex differences in the burden and progression of cerebrovascular disease and in the pathogenesis of NCI in PWH, which will inform the rational design of clinical trials, including the target study population, in which to test interventions to prevent and treat NCI in PWH.