Summary/Abstract HIV infection has been associated with multiple cardiovascular comorbidities, including atherosclerotic cardiovascular disease and heart failure. Our long-standing work focusing on subclinical cardiovascular measures (e.g., carotid artery atherosclerosis and cardiac dysfunction) in the Women’s Interagency HIV Study (WIHS) and Multicenter AIDS Cohort Study (MACS) (now as a Combined Cohort Study, MWCCS) have provided insights into the effects of HIV infection, along with chronic inflammation, immune activation, and antiretroviral therapy (ART) on multiple cardiovascular comorbidities. However, the underlying pathogenesis of these interrelated cardiovascular comorbidities, and especially their shared biological mechanisms, is not fully understood. Our existing work among WIHS women has identified several gut bacteria and related host immunological markers and microbial metabolites associated with carotid artery atherosclerosis. In this study, we propose to extend our multi-omics work to the MWCCS and expand our cardiovascular outcomes to multiple vascular and cardiac phenotypes measured through carotid artery ultrasound (carotid artery plaque, arterial stiffness) and echocardiography (left ventricular [LV)] systolic dysfunction, LV diastolic dysfunction and LV longitudinal strain). Using a novel multi-faceted analysis among up to 2000 participants (~65% of whom are HIV+), we propose to apply our multi-omics approaches (metagenomics, transcriptomics, proteomics, metabolomics) to identify common gut microbial alterations associated with multiple vascular and cardiac measures and examine their underlying mechanisms in the context of HIV infection. In addition, we will examine how HIV infection and HIV-specific factors (e.g., long-term specific ART, persistent viremia, CD4 counts) may influence cardiovascular phenotypes through alterations in gut microbiota and related immunologic and metabolomic features. Findings from this study will improve understanding of common, overlapping etiologies underlying the multiple cardiovascular comorbidities associated with HIV infection. These findings will also identify potential therapeutic targets (e.g., microbiota modification) applicable to various cardiovascular disorders for which current treatments are only partially effective or lacking in this and other high-risk populations.