PROJECT SUMMARY/ABSTRACT The capacity of pre-existing antibody (Ab) responses to protect from infection is a paradigm of modern vaccinology. Central to this is the idea that Abs have specific targets and functions that impart protective capacity. Some animal models and studies of HIV-infected individuals suggest that antibody dependent cellular cytotoxicity (ADCC), which leads to elimination of infected cells, may protect against HIV transmission and/or pathogenesis, but studies are limited overall. Although animal models can provide insight into mechanisms of protection, they often rely upon high challenge doses of a single viral variant, which does not reflect the setting of natural HIV transmission. Few studies have examined in humans whether pre-existing ADCC Abs, either vaccine-elicited or passively-transferred, influence HIV transmission or pathogenesis. There is also variation in human studies on whether Abs targeting specific epitopes are critical for protection and whether such epitopes are recognized by ADCC-mediating Abs, information which is critical to harnessing these findings for vaccine development. As maternal Abs are passively transferred to the infant circulation late in pregnancy and before breastfeeding exposure to HIV, mother to child transmission (MTCT) represents a rare, natural setting in which to gauge the correlates of protection against HIV acquisition and disease progression. This project proposes to study breastfeeding MTCT in order to provide more relevant human data on the influence of pre-existing and HIV-specific Abs on HIV acquisition and pathogenesis. This proposal will specifically address the hypothesis that pre-existing and passively-transferred maternal antibodies targeting specific epitopes and that mediate ADCC protect infants from MTCT and HIV pathogenesis. In Aim 1, the role of maternally-derived ADCC on MTCT and subsequent HIV+ infant clinical outcome among two cohorts of breastfeeding infants will be evaluated, expanding previous work to a novel cohort and using two distinct assays to measure plasma ADCC activity. In Aim 2, the plasma targeted HIV epitopes associated with MTCT risk will be identified using a high-throughput and high- resolution phage-display approach. Aim 3 will focus on a specific mother/infant pair to isolate HIV-specific B cells and thereby more deeply characterize one example of HIV-specific and ADCC-mediating Abs in a setting where infant clinical outcome was more favorable over a two-year follow-up period. Together, these aims will contribute to an increased understanding of the Ab properties that can curb HIV transmission and pathogenesis, thereby providing characterized end-points to improve HIV vaccine and therapeutic development. In addition to the proposed research, this fellowship will support the professional development of the investigator through training in state-of-the-art techniques, collaborating with experts in computational biology and statistics, presenting at...