HIV-1 infection in infants persists at high rates despite efforts to prevent perinatal transmission. In 2022, an
estimated 130,000 new perinatal HIV-1 infections were reported globally. Antiretroviral therapy (ART) is
lifesaving for these infants. However, HIV-1 creates a hidden pool of proviruses that escape HIV-1 treatment
and cause the virus to rebound. These proviruses make it necessary for children and adults to require lifelong
ART. Novel therapeutic interventions such as very early antiretroviral treatment of newborns or combining ART
with broadly neutralizing antibodies (bNAbs) are under study in the International Maternal Pediatric Adolescent
AIDS Clinical Trials (IMPAACT) Network. These studies aim to restrict HIV-1 reservoir size to achieve ART-free
remission in neonates and infants. The proposed project will characterize proviral pool composition in neonates
and infants with HIV-1 initiating ART-free remission treatments. It will also investigate the proviral pool's
contribution to viremic rebound during therapy and analytic treatment interruption (ATI). We hypothesize that
achieving ART-free remission in infants depends on the proportion of intact proviruses and their integration
sites at treatment initiation, along with their clearance susceptibility through very early and enhanced early
treatment. We further hypothesize that clonal expansion contributes to a high proviral load before treatment
and governs the time to rebound viremia on and off ART. The Specific Aims of this proposed project are to (1)
Quantify and characterize the intact proviral pool in neonates and infants receiving very early and enhanced
early therapies toward HIV-1 ART-free remission; (2) Evaluate HIV integration sites, clonal abundance of
infected cells, infection dynamics in prenatal and early postnatal life, and viral clearance under ART
interventions; (3) Assess the potential to improve bNAb susceptibility testing in neonates and infants to fully
determine the selection and persistence of bNAb resistance during ART-free remission therapies. We plan to
use cutting-edge approaches using near full-length single genome sequencing (nFLSGS) and integration site
analyses on proviral DNA, along with a pan-subtype IPDA on genomic DNA from peripheral blood mononuclear
cells (PBMCs) collected during therapy in two NIH-sponsored pediatric clinical trials involving very early
treatment of neonates and infants in combination with broadly neutralizing antibodies, IMPAACT P1115 and
2008. We will also comprehensively assess the provirus susceptibility to a panel of bNAbs and their escape
potential during bNAb therapy. The resulting data will fill a critical gap in understanding HIV-1 bNAb efficacy for
neonates and infants globally.
