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.
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.
|King, Caroline C; Kourtis, Athena P; Persaud, Deborah et al. (2015) Delayed HIV detection among infants exposed to postnatal antiretroviral prophylaxis during breastfeeding. AIDS 29:1953-61|
|Luzuriaga, Katherine; Tabak, Barbara; Garber, Manuel et al. (2014) HIV type 1 (HIV-1) proviral reservoirs decay continuously under sustained virologic control in HIV-1-infected children who received early treatment. J Infect Dis 210:1529-38|
|Persaud, Deborah; Patel, Kunjal; Karalius, Brad et al. (2014) Influence of age at virologic control on peripheral blood human immunodeficiency virus reservoir size and serostatus in perinatally infected adolescents. JAMA Pediatr 168:1138-46|
|Persaud, Deborah; Gay, Hannah; Ziemniak, Carrie et al. (2013) Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med 369:1828-35|