ABSTRACT More than $50 billion has been invested to expand access to antiretroviral therapy (ART) for people living with HIV (PLWH) in sub-Saharan Africa. Yet, regional HIV programs largely overlook causes of non-AIDS morbidity, thereby threatening to undermine the tremendous gains achieved. In the US, coronary artery disease (CAD) is significantly more common among PLWH than HIV-uninfected individuals. However, determinants of CAD among PLWH in the US are unlikely to generalize to rural Africa, due to unique environmental, inflammatory, and social risk factors. For example, in an NHLBI R21-funded pilot, we enrolled a cohort of PLWH on ART in rural Uganda and population-based, HIV-negative controls, and demonstrated that PLWH have greater rates of arterial stiffness and electrocardiographic abnormalities despite having lower blood pressure, lower low density lipoprotein and lower rates of active smoking. We also identified inflammatory pathways in Uganda, such as the kynurenine:tryptophan ratio, which differ by sex, and correlate more strongly with atherosclerosis and mortality in Uganda than the US. We now propose to augment our established research infrastructure with contrast enhanced computed tomography of the coronary arteries, to directly and non-invasively measure the impact of HIV on CAD in rural Uganda, and identify regional determinants of CAD through the following aims: Aim 1: Determine whether CAD is more prevalent and severe among PLWH than HIV-uninfected comparators in rural Uganda. We will complete coronary CT angiography in 600 participants, and compare the prevalence and severity of CAD between PLWH and HIV uninfected comparators. Hypothesis: PLWH in Uganda have a higher prevalence and severity of CAD compared to HIV-uninfected comparators. Aim 2: Determine the extent to which the association between HIV infection and CAD is modified by sex and region. Within our cohort, we will test for effect modification by sex (Aim 2a). Then, by pooling our data with US data from PLWH enrolled in the REPREIVE study, we will test for effect modification by country of origin (Aim 2b). Hypothesis: The association between HIV infection and CAD is greater among women (vs. men) and among PLWH in Uganda (vs. PLWH in the US). Aim 3: Identify regional correlates of CAD, and develop a risk prediction score for the presence of CAD among PLWH in rural sub-Saharan Africa. We will collect data on traditional (e.g. age, smoking, diabetes), HIV-specific (e.g. macrophage activation, CD4 count, ART history), and region-specific factors (e.g. biomass exposure, tuberculosis history, K:T ratio). In Aim 3a we will include traditional, HIV-specific and regional risk factors in models to identify correlates of CAD. In Aim 3b, we will propose a simplified risk score to identify PLWH with CAD. Hypothesis: Non-traditional risk factors provide substantive explanatory power for estimating CAD risk beyond traditional factors typically used in risk prediction models in ...