DESCRIPTION (provided by applicant): In early-treated children, HAART leads to a unique state of viral persistence whereby HIV replication is controlled solely by antiretroviral drugs wit little HIV-specific immunity (elite-treatment responders). We hypothesize that long-term early effective therapy of infants may promote a state of HIV persistence that is distinct from long-term treated adults that is comprised of negligible levels of proviral DNA, a nondetectable resting CD4+T cell latent replication-competent viral reservoir, absent residual viremia, HIV specific immune responses, immune activation and inflammation. In the context of the PHACS/AMP study, we will measure the following in a cohort of preadolescent pediatric long-term elite treatment responders: 1) Determine the long- term effects of early HAART on the size of proviral and replication-competent HIV reservoirs in perinatally HIV- infected pre-adolescents and adolescents treated from infancy, 2) Examine the long-term effects of early HAART from infancy on the dynamics of HIV persistence and immune outcomes in perinatally HIV-infected pre-adolescents and adolescents, and 3) Determine the long-term effect of early HAART on diversity of proviral and replication-competent HIV reservoirs in pre-adolescents and adolescents treated from infancy. The proposed project will improve scientific knowledge on the long-term virologic and immunologic effects of early HAART for infants who are now likely to survive to young adulthood and provide a critical framework for defining HIV CURE in clinical trials aimed at achieving HIV CURE for children and adolescents.

PUBLIC HEALTH RELEVANCE: Relevance Understanding the pathogenesis of HIV persistence in children who maintain control of virus replication in the absence of HIV-specific immunity would provide quantitative insights into HIV persistence not under immune control that may help define mechanisms of HIV persistence. Elite treatment responders of pre- adolescents may be an ideal population for testing novel treatment strategies aimed at purging viral reservoirs, including therapeutic vaccinations. If, through the specific aims outlined in this proposal, a unique composite biomarker profile is identified that renders HIV infection inactive, this finding can be further validated in already existing, well-characterized cohorts of early-treated children internationally. The eventual long-term objective is to improve understanding of HIV persistence in children to assist with treatment strategies aimed at HIV CURE for pediatric populations.