Abstract The burden of HIV among adolescents and young adults remains high with more than 30% of new HIV infections globally occurring among youth ages 15 to 24 years, making this a critical target population for prevention strategies. While induction of broadly neutralizing antibodies (bnAbs), is a major goal for an HIV vaccine, none of the candidate vaccines tested to date has been able to generate this sort of response. Remarkably, recent studies have indicated that HIV infected children develop broad neutralization earlier and more frequently than adults. To confirm these findings, we recently compared neutralizing antibody responses in a large cross-sectional cohort of HIV infected children aged 1-3 years old to that of chronically infected adults. By one year of age, the neutralization breadth in children was comparable to that of adults, confirming that HIV infected children are able to develop broad neutralization early. Interestingly, contrary to adults in which neutralization breadth is usually mediated by bnAbs of one or two specificities, in the majority of children, neutralization appeared to be mediated by a polyclonal response. This suggests that different mechanisms could drive the development of neutralization breadth in children and adults. Importantly, a recent transcriptome analysis revealed an association between the expression of a protein that regulates natural killer (NK) cell function (RAB11FIP5) and bnAb development in HIV-infected adults. Early life NK cells are functionally different from adults NK cells; and it is well established that the early life immune milieu is distinct from that of adults. Yet, whether the distinct early life immune environment or the expression of specific factors such as RAB11FIP5 are associated with early broad neutralization development in young children remains unknown. In this study, we therefore propose to test the hypothesis that a distinct host transcriptional profile is associated with the development of HIV-specific antibody neutralization breadth in early life, using archived, longitudinal samples from HIV-infected children enrolled in the Mother and Infant cohort study (MICS) and the NICHD International Site Development Initiative Pediatric study (NISDI). Our specific aims are: 1) To define the kinetics of development of broad neutralization in a longitudinal cohort of HIV-infected children; and 2) To evaluate the association between transcriptional profile and development of neutralization breadth in HIV-infected children. This study will enhance our current understanding on the kinetics of neutralization breadth development in HIV-infected children and provide novel insights on the molecular pathways leading to neutralization breadth development early in life. Altogether, this new information will guide the development of HIV vaccine strategies designed to protect prior to sexual debut. In addition, transcriptional signatures of broad neutralization could serve as markers for the...