ABSTRACT While the use of antiretroviral therapy (ART) to treat HIV-1-infected mothers has reduced the rate of mother-to-child transmission (MTCT) of HIV, HIV-exposed, uninfected (HEU) infants still face numerous health risks, including risk of mortality, developmental deficits, and severe infections. In particular, HEU infants face increased susceptibility to perinatal viral infections including congenital cytomegalovirus (CMV) and neonatal herpes simplex virus (HSV). Congenital CMV infection is a leading cause of sensorineural hearing loss and permanent neurologic deficits, and neonatal HSV-1/2 can result in severe sepsis, devastating neurological deficits, and death. Thus, there is significant need to protect HIV-exposed infants against these viruses, including the development of prophylactic and treatment strategies for HSV and CMV. Currently, the primary causes for this increased risk of perinatal herpes virus infections in HEU infants remain unexplored. We hypothesize that (1) HIV-infected mothers have impaired HSV/CMV-specific IgG responses, including protective antiviral functions such as antibody- dependent cellular cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), and virus neutralization and (2) in the context of HIV, these maternal antibodies are variably transplacentally transferred to the infant, leaving HEU infants at higher risk for severe perinatal infections. This study aims to define the placental transmission rate of and characteristics of CMV and HSV-specific IgG in HIV-infected pregnant women and their infants. Furthermore, this study will define the humoral immune correlates of protection against congenital CMV transmission. The investigation of maternal antibodies will include the identification of Fc region characteristics associated with efficient placental IgG transfer and assessment of the role of antiviral antibody functions in perinatal virus transmission, including neutralization, ADCC, and ADCP. This work will establish the immunologic basis for increased risk for CMV and HSV infections in HEU infants, and importantly, will provide insight into rational vaccine design to ultimately reduce the risk and severity of congenital CMV and neonatal HSV infections for all children.