Project Grant R01AI183381

HIGH RESOLUTION INFLAMMATORY NETWORKS INDUCED BY HIV RESERVOIRS IN ADOLESCENTS - ABSTRACT ANTIRETROVIRAL TREATMENT (ART) FOR HIV INFECTION EFFECTIVELY BLOCKS VIRAL REPLICATION, BUT FAILS TO ERADICATE THE VIRUS, WHICH CAN BE A SOURCE OF PERSISTENT INFLAMMATION. THE PATHWAYS BY WHICH CHRONIC, TREATED HIV INFECTION DRIVES INFLAMMATION ARE POORLY DEFINED, PARTICULARLY IN CHILDREN AND ADOLESCENTS WHO ACQUIRE HIV PERINATALLY. PERINATAL HIV INFECTION OCCURS IN THE CONTEXT OF A DEVELOPING IMMUNE SYSTEM, REQUIRES LIFE-LONG TREATMENT, AND EVEN WITH EFFECTIVE ART, TREATMENT IS ASSOCIATED WITH INCREASED RISKS OF METABOLIC, NEUROCOGNITIVE AND CARDIOVASCULAR COMPLICATIONS THAT RESULT FROM THIS HIV-INDUCED INFLAMMATION. THUS, TO UNDERSTAND THE MECHANISMS DRIVING INFLAMMATION IN THIS VULNERABLE POPULATION THAT FACES DECADES-LONG INFECTION AND TREATMENT, WE WILL STUDY HIV-INDUCED INFLAMMATION IN A UNIQUE COHORT OF PERINATALLY INFECTED ADOLESCENTS IN KENYA WHO HAVE BEEN MAINTAINED ON ART AND FOLLOWED CLINICALLY SINCE THEIR FIRST YEAR OF LIFE. TO COMPLEMENT THESE VALUABLE LONGITUDINAL CLINICAL SAMPLES, WE HAVE DEVELOPED ORGANOIDS OF HUMAN SECONDARY LYMPHOID TISSUES, A MAJOR HIV RESERVOIR SITE. THE LYMPHOID ORGANOIDS WE ARE USING ARE HIGHLY RELEVANT TO PEDIATRIC AND ADOLESCENT INFECTIONS AS THEY ARE DERIVED FROM PEDIATRIC/ADOLESCENT TISSUE, CONTAIN ALL MAJOR IMMUNE CELL TYPES, INFECTABLE WITH HIV, AND ARE MANIPULABLE VIA GENE EDITING, SIRNA TRANSFECTION, AND ANTIBODY/SMALL MOLECULE INHIBITORS TO PROBE MECHANISMS DRIVING HIV-INDUCED INFLAMMATION. OUR GOAL IS TO USE THESE UNIQUE RESOURCES TO IDENTIFY HIV-INDUCED INFLAMMATORY NETWORKS IN PERINATALLY-INFECTED ADOLESCENTS ON LONG-TERM ART AND TO DEFINE THE VIRAL FACTORS THAT DRIVE HIV-INDUCED INFLAMMATION. WE WILL MAKE USE OF SINGLE CELL TECHNIQUES, WHICH TO DATE HAVE ONLY BEEN APPLIED TO ADULT COHORTS, TO MAP THE CELL-INTRINSIC INFLAMMATORY NETWORKS INDUCED DURING CHRONIC TREATED HIV INFECTION AND DEFINE THE VIRAL GENES THAT INITIATE THESE CASCADES. IN ADDITION, TO FILL A GAP THAT HAS BEEN MISSING IN PRIOR STUDIES, WE SEEK TO UNDERSTAND HOW THESE RARE INFECTED CELLS INITIATE DOWNSTREAM CASCADES OF INFLAMMATION THAT DRIVE PATHOLOGY BY STUDYING COMMUNICATION NETWORKS USING METHODS WE RECENTLY DEVELOPED TO INFER CELL-CELL COMMUNICATION AT THE SINGLE CELL LEVEL. THIS POWERFUL COMBINATION OF A LONG-TERM PEDIATRIC TREATMENT COHORT COUPLED WITH MECHANISTIC STUDIES IN A ROBUST EX VIVO LYMPHOID CULTURE SYSTEM WILL PROVIDE A UNIQUE WINDOW INTO HIV-INDUCED INFLAMMATION. SUCCESSFUL COMPLETION OF THIS PROJECT WILL DEFINE MECHANISMS BY WHICH RESIDUAL HIV RNA EXPRESSION DURING TREATED INFECTION DRIVES INFLAMMATION IN PERINATALLY INFECTED ADOLESCENTS AND ESTABLISH MODELS TO TEST THERAPEUTICS.