PROJECT SUMMARY Significance: Antiretroviral medications (ARVs) to treat and prevent HIV infection in reproductive-aged women have been a landmark public health success, having averted millions of pediatric HIV infections. In addition to taking ARVs as HIV treatment, pregnant women are increasingly taking ARVs as pre-exposure prophylaxis (PrEP) against HIV infection. However, recent studies have shown that ARVs in pregnancy may also confer risks to the developing placenta and fetus. Low placenta weight, placental insufficiency, and maternal vascular malperfusion are more common among WHIV taking ARVs compared to WHIV not taking ARVs, and WHIV initiating ARVs pre-conception have a 35% higher risk of having a small-for-gestational-age baby than WHIV initiating ARVs post-conception. ARVs are life-saving HIV therapy and prevention, but PrEP safety in pregnant women, their fetuses, and their offspring is unknown. Information about the safety of PrEP in pregnancy is urgently needed to improve selection and management of ARVs as PrEP and HIV treatment during this high- risk time. Innovation: We propose the first study to simultaneously compare placenta structure, angiogenesis, and metabolic capacity between HIV-uninfected women taking ARVs as PrEP, WHIV taking ARVs, and HIV- uninfected women taking no ARVs to determine the independent effects of ARVs and HIV on the placenta. Distinct advantages of our proposed research include 1) simultaneous collection and comparison HIV-exposed and -unexposed and ARV-exposed and -unexposed placentas, and 2) longitudinal observation of all children over the first 12 months of life to relate placental findings to birth weight and infant growth. Investigators: Our interdisciplinary team with expertise in placental pathology and HIV epidemiology (PI Bebell, an early career NIAID K23-funded investigator), translational laboratory work on the placental effects of HIV and antiretrovirals (Co-I Serghides), biostatistics (Co-I Rabideau) and maternal health (contributor Ngonzi), is well-poised to complete this work. Approach: We will leverage stored placental and plasma samples from the PI's ongoing NIH Career Development Award (K23AI138856) cohort in Uganda, clinical data from enrolled women and their children, and Dr. Serghides' established laboratory infrastructure to elucidate the independent effects of HIV and ARV exposure on the placenta and potential contribution of these changes to early child growth through these specific aims: 1) Compare placental structure and angiogenesis by maternal ARV and HIV exposure status. 2) Compare placental metabolic capacity by maternal ARV and HIV exposure status. 3) Determine the effects of placental structure and metabolic capacity on birth weight and infant growth. Identifying mechanisms of ARV-related placental toxicities has great potential to improve pregnancy outcomes through optimized PrEP and ART regimens. Using data gathered we will submit an R01 proposal to investigate placenta...