PROJECT SUMMARY Background: Successful mother-to-child HIV transmission prevention programs have decreased the global incidence of congenital HIV. Yet, >1 million HIV-exposed, uninfected (HEU) children are born annually in sub- Saharan Africa and have poorer early-life outcomes than HIV-unexposed children. The pathophysiology of these poor outcomes is poorly understood, yet critical to developing effective interventions to improve outcomes for these children. I hypothesize that placental inflammation may contribute to adverse HEU child health outcomes by decreasing quality and quantity of transplacental antibody transfer and disrupting normal pathogen barrier functions. Candidate: My overarching career goal is to become an independent, NIH-funded clinical investigator with expertise in the contribution of maternal infections, the placenta, and inflammation to health outcomes of HIV-exposed children. My clinical work caring for women living with HIV (WLWH) and their infants and conducting research investigating maternal-child health outcomes has inspired this career path. I am well-prepared to undertake the scientific and training aims proposed here, having successfully published eight first-author manuscripts and completed a 50-placenta histology pilot study in Uganda in 2016. Mentoring: Dr. Ingrid Bassett (Primary Mentor) is an NIH-funded investigator who has successfully mentored 4 NIH K23 awardees. Dr. Drucilla Roberts (Co-mentor, Pathology) has been a perinatal pathologist for nearly 30 years and worked in Africa for over a decade. Drs. Mark Siedner (Global Health), Galit Alter (Immunology), Joseph Ngonzi (Uganda Site), Roger Shapiro (HEU Outcomes), Bethany Hedt-Gauthier (Biostatistics), and Elias Kumbakumba (Infant Outcomes) will provide additional focused mentorship to ensure my success. Research: I will enroll a prospective cohort of 300 WLWH on ART in late pregnancy and a comparison group of 150 HIV-uninfected pregnant women in Uganda and collect their placentas at birth. I will compare the prevalence of inflammatory placental abnormalities by maternal HIV serostatus and determine the correlates of inflammatory placental abnormalities in WLWH. Potential correlates include maternal factors (CD4 count, ART regimen, CMV viremia) and placental factors (detectable placental HIV and placental infections). I will measure transplacental respiratory pathogen antibody transfer as surrogate immune measures of placental function, and follow infants born to enrolled women for 12 months to determine the association of inflammatory placental abnormalities with HEU infant morbidity and mortality. Training: To achieve my aims and gain research independence, I require additional training in: 1) placental histopathology, biology, and immunology 2) causal inference theory, with a focus on mediation analysis, and 3) clinical trial design to conduct a larger R01-funded study of placental inflammation in Uganda. Based on my previous research experience and success, support from an exceptional mentoring team, strong institutional commitment, and an innovative research plan, I am well-positioned to become an independent clinical investigator focused on maternal-child health in WLWH.

PROJECT NARRATIVE Successful mother-to-child HIV transmission prevention programs have decreased the number of children born with HIV. However, the >1 million HIV-exposed but uninfected children born annually in sub-Saharan Africa have poorer early-life outcomes than HIV-unexposed children. By enrolling mother-infant pairs in Uganda, I propose to study whether placental inflammation is more common in women living with HIV than HIV- uninfected women; what infections, medications, and maternal health conditions drive placental inflammation; and whether placental inflammation is linked to poor child health outcomes in HIV-exposed infants.