Project Summary/Abstract: People living with HIV are at increased risk of cardiovascular and metabolic complications compared to HIV-uninfected control populations. Compared to what is known in older adults, little is known about these risks in adolescents and young adults and even less in the setting of sub-Saharan Africa. Although inflammation has been linked to cardiovascular disease in adults with HIV, the role of alteration in gut integrity and environmental factors on metabolic complication has been scarcely investigated in youth living with HIV. Furthermore, the impact of non-AIDS co morbidities may be greater in sub-Saharan Africa, though no studies of metabolic complications have been conducted in youth on ART in this setting. The overall objective of this proposed R21 research plan is to use surrogate markers of gut integrity, microbial translocation and inflammation to understand the mechanisms underlying adiposity and insulin resistance in youth living with HIV, so that risk-reduction therapies can be appropriately targeted and novel preventive strategies may be developed in the future. In a cross-sectional study of 100 adolescents and young adults living with HIV and 100 uninfected controls, this project aims to measure biomarkers of gut integrity and bacterial translocation to identify ongoing evidence of a “leaky gut” in youth living with HIV compared to age and gender match HIV uninfected controls in Kampala, an urban setting, and Gulu, a rural setting Uganda. We will investigate whether these measures of gut integrity and bacterial translocation correlate with metabolic disease using DXA scan to measure adiposity and insulin resistance. Additionally, we will examine the role of environmental, nutritional and socioeconomic factors that may differ between urban and rural settings and their associations with markers of gut integrity and microbial translocation. This study will provide a comprehensive view of how gut integrity, bacterial translocation and inflammation relate to metabolic disease among adolescents and young adults living with HIV and the role that important environmental and social differences play in urban versus rural settings in Uganda. The PI, Dr Dirajlal-Fargo, is an exceptional candidate who is seeking to become an internationally recognized clinician-investigator in the field of cardiometabolic complications in pediatric HIV. She also has extensive experience conducting clinical research in Uganda. Dr Dirajlal-Fargo has strong institutional support from Case Western Reserve University and the Department of Pediatrics at Rainbow Babies and Children’s Hospital. She will have access to a wealth of resources that will ensure a successful transition to independently funded investigator.