Project Summary/Abstract: There are 2.1 million children under 15 years living with HIV worldwide; the vast majority have perinatally acquired HIV (PHIV) and reside in Eastern and Southern Africa. Children living with PHIV are now expected to live through adolescence and well into adulthood, such that adolescents now represent the largest growing population living with HIV. Several comorbidities, including cardiometabolic, have been associated with heightened immune activation and inflammation despite viral suppression in adults living with HIV. Because of the small size and paucity of pediatric data, controversy exists regarding the mechanisms and the extent to which heightened inflammation should be concerning in this young population during formative years. Lipidomics analyses have revealed associations of lipid classes and fatty acid composition with inflammation and several diseases, including cardiometabolic complications. The overall goal of this project is to obtain new insight into PHIV and the factors associated with immune activation and subclinical cardiovascular disease. We will use novel unbiased analysis of integrated lipidomic and bring an innovative approach to identify signaling cascades related to lipid processing that may predict cardiovascular complications in PHIV. In a longitudinal study of 100 PHIV and age-and sex-matched uninfected controls, this project aims to measure the lipidome over 96 weeks to identify lipid perturbations associated with HIV and pathways associated with immune activation. We will investigate whether pro- inflammatory lipids are predictive of subclinical vascular disease. Additionally, we will examine the role of specific ART classes as well as individual antiretroviral drugs on the lipidome. The proposed study leverages the rich data of Dr. Dirajlal-Fargo’s K23 study in Uganda. This study will build on the well-phenotyped cohort of virally suppressed adolescents with PHIV and age-and sex- matched uninfected comparison group and utilize repository specimens. The longitudinal design will allow for data validation and replication, a major criticism of prior observational omics studies. This study may reveal novel biomarker signatures of biological, clinical, and prognostic relevance to prevent cardiovascular disease for adolescents who are advancing into adulthood and have received long-term ART.