Project Grant R01AI186792

IMPACT OF NEONATAL ART AND BROADLY NEUTRALIZING ANTIBODIES ON HIV-1 RESERVOIRS IN INFANTS: TOWARDS ART-FREE REMISSION - 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.