Project(Summary( With the global implementation of prenatal antiretroviral therapy (ART), over 18 million individuals born to mothers with HIV have been HIV-exposed but uninfected (HEU). While HEU infants and children are known to be at increased risk of adverse health outcomes, the long-term implications of in utero HIV/ART exposure into adulthood have not been well explored. The candidate has generated novel preliminary data to show an increased prevalence of obesity in HEU adolescents and young adults versus well-matched controls. These findings convey the compelling need to characterize the extent of metabolic and immune dysregulation among HEU young adults, and to delineate molecular pathways that may underlie this phenotype. Candidate: Dr. Fourman is an endocrinologist and clinical investigator at Harvard Medical School dedicated to identifying novel mechanisms and treatment strategies for metabolic disease. Her work thus far has centered on metabolic complications of HIV. Her overarching career goal is to become an independent R01-funded clinical investigator committed to preventing and treating obesity and metabolic disease in the rapidly growing HEU population, as well as in other groups exposed to abnormal intrauterine environments. Training: To achieve this goal, Dr. Fourman has developed a career development plan that will provide targeted training in developmental origins of health and disease (DOHaD), immunologic aspects of metabolic disease, design and interpretation of epigenetic studies, and social and behavioral determinants of health. Mentors: The candidate's career development and research plans will be overseen by her primary mentor, Dr. Steven Grinspoon, who is an internationally recognized leader in metabolic disease research in HIV. The applicant also will be supported by a highly invested team of co-mentors and advisors with expertise in DOHaD, epigenetics, immunology, infectious diseases, epidemiology, and biostatistics. Research: Dr. Fourman will leverage her background in endocrinology and HIV to test the innovative hypothesis that the HIV intrauterine environment influences fetal development to confer an increased susceptibility to metabolic and immune dysregulation later in life. Specifically, she will conduct the first prospective study that compares long-term health outcomes in HEU young adults versus well-matched controls. In Aims 1-2, Dr. Fourman will delineate the downstream metabolic and immune sequelae of in utero HIV/ART exposure among HEU young adults. In Aim 3, she will investigate the contribution of epigenetic modifications to the HEU phenotype. This project stands to establish in utero HIV/ART exposure as a previously unrecognized risk factor for metabolic disease. Only by defining long-term metabolic and immune perturbations among the HEU population can screening and prevention strategies be optimized for this group. Furthermore, this Award will launch Dr. Fourman on an independent career trajectory, distinct from that of her mentors, to not only advance the health of the HEU population, but also to investigate the developmental origins of metabolic disease in diverse clinical contexts.