ABSTRACT: HIV-exposed but uninfected (HEU) infants are twice as likely to die as HIV-unexposed and uninfected infants (HUU), mainly from other infectious diseases. There is an urgent need to understand how maternal HIV infection?whether controlled or not? impacts the development of the neonatal immune system. With this information, we can develop algorithms to prevent infectious diseases in HEU that account for their functional immune deficits. We hypothesize that maternal HIV infection results in inflammation of the placenta, decreased maternal-to- child transfer of antibodies, and differential programming of the neonatal immune system that impairs the immune response to vaccines. To test this hypothesis, we will integrate clinical data with immunologic data we will obtain from maternal, placenta and neonatal samples that were collected as part of an NIH-funded R01 study we have been conducting in India since 2014. We enrolled a unique, well-defined cohort of maternal- infant pairs with and without HIV and followed them longitudinally through pregnancy and the first year postpartum. We propose to capitalize on these stored samples to address the following aims: Aim 1. Compare the Treg/CD8+ T cell ratio in maternal blood, placenta, and cord blood samples by maternal HIV status and viral load. This aim will establish the relationship between immune cells and cytokines in maternal blood, placenta and cord blood samples, using flow cytometry, immunecard technology and immunohistochemical staining. Understanding how maternal and placental immunology relate to neonatal immune development may help us predict which infants will have impaired immune responses to pathogens. Aim 2. Determine the effect of placental immune function on infants? humoral and cellular immunity. This aim will (1) identify how HIV decreases the transplacental transfer of antibodies to key respiratory pathogens involved in HEU infant mortality, including S. pneumoniae, H. influenzae, and influenza virus; and (2) determine if placental inflammation impacts the longevity of the infant?s immune response to BCG vaccine. Using these data, we can develop screening tests to predict which neonates will have the greatest immune compromise at birth. Studying the role of the placenta in the development of the neonatal immune system may also reveal key differences between HEU and HUU infants that will allow us to optimize care for this vulnerable population.