Grant: Project Grant

The use of HIV medications in pregnancy has enabled a radical reduction in the rate of perinatal HIV transmission. As a consequence, there is now a growing number of children who are born HIV-exposed but uninfected (HEU). While most children who are HEU are in good health, studies suggest that these children may experience some health problems and development delays, in part due to exposure to the HIV drugs during pregnancy. The risk of toxicity to the fetus from the HIV drugs is likely related to how much drug is transferred from the mother to the fetus. Drug transporters and metabolic enzymes are specific cell proteins that play a significant role in the transfer and/or degradation of drugs from the mother to the fetus. Evidence from animal studies suggest that placental and fetal expression levels of transporters and metabolic enzymes can vary during gestation. In addition, sex has been identified as an important factor that can influence expression levels of these drug transporters and enzymes in adult humans and rodents, however whether this happens in the fetus is not well known. In this study, we propose to determine the expression levels and localization of these drug transporters and metabolic enzymes in human and rodent placentas and fetuses across gestation and compare these levels in female and male fetuses. We will also investigate the transfer of commonly used HIV drugs from mother to fetus and assess potential fetal toxicities in non-infected and HIV-infected mouse models (i.e., EcoHIV model), as well as examine potential sex differences. Overall, this study will provide novel information on the ontogeny of drug transporters and metabolic enzymes along with the extend of antiviral drug fetal transfer and risks of potential fetal drug toxicities.