HIV-1 ENVLRS: A SCALABLE, SEQUENCE-BASED ASSAY FOR IN-DEPTH ASSESSMENT OF HIV-1 BNAB RESISTANCE - PROJECT SUMMARY/ABSTRACT HUMAN IMMUNODEFICIENCY VIRUS TYPE-1 (HIV-1) IS A RETROVIRUS THAT INFECTS CD4+ T CELLS OF THE IMMUNE SYSTEM. IF LEFT UNTREATED, PEOPLE LIVING WITH HIV-1 (PLWH) WILL PROGRESS TO AIDS AND MAY ULTIMATELY DIE AS A RESULT. COMBINATION ANTIRETROVIRAL THERAPY (ART) WITH SMALL-MOLECULE DRUGS IS EXTREMELY EFFECTIVE AT STOPPING THE REPLICATION OF HIV-1 IN INFECTED INDIVIDUALS BUT REQUIRES DAILY DOSING OFTEN WITH CONSIDERABLE SIDE EFFECTS. IMPORTANTLY, DESPITE THE SUCCESS OF THIS APPROACH AT SUPPRESSING HIV-1 REPLICATION TO CLINICALLY UNDETECTABLE LEVELS, ANTIRETROVIRAL THERAPY IS NOT CURATIVE. THIS IS DUE TO THE PERSISTENCE OF HIV-1 IN A SILENT, OR LATENT, STATE WITHIN LONG-LIVED CD4+ T CELLS AT EXTREMELY LOW FREQUENCIES. THESE LATENTLY INFECTED CELLS ARE NOT TARGETED BY CURRENT SMALL-MOLECULE ART REGIMENS. AS A RESULT, PLWH MUST REMAIN ON LIFELONG ANTIRETROVIRAL THERAPY. BROADLY NEUTRALIZING ANTIBODIES TARGETING CRITICAL EPITOPES IN HIV-1 ENV (HIV-1 BNABS) ARE CURRENTLY BEING DEVELOPED AS A POTENTIAL APPROACH TO ELIMINATE LATENT HIV-1 AND/OR AS AN ALTERNATIVE TO SMALL-MOLECULE ART. HIV-1 BNABS OFFER SEVERAL ADVANTAGES OVER TRADITIONAL SMALL-MOLECULE ART, INCLUDING THE POTENTIAL FOR LONG-ACTING FORMULATIONS, REDUCED SIDE EFFECTS, AND THE POTENTIAL TO ELIMINATE LATENTLY INFECTED CELLS OVER TIME. HOWEVER, A MAJOR CHALLENGE TO THE IMPLEMENTATION OF HIV-1 BNABS IN TREATMENT AND CURE IS PRE-EXISTING VARIATION OR RESISTANCE IN THE BNAB-TARGETED EPITOPES. SCALABLE CLINICAL TESTS ARE NEEDED TO DETERMINE (1) WHETHER PEOPLE WHO WILL RECEIVE HIV-1 BNABS HAVE PRE-EXISTING RESISTANCE, AND (2) PERSONALIZE HIV-1 BNAB COMBINATIONS TO EACH INDIVIDUAL. TO ADDRESS THIS CRITICAL UNMET NEED, ACCELEVIRDX IS DEVELOPING THE HIV-1 ENVLRS ASSAY AS THE FIRST SCALABLE SEQUENCE-BASED TEST TO ASSESS HIV-1 BNAB RESISTANCE AND PREDICT ANTIBODY EFFICACY BY IN-DEPTH ENV SEQUENCE ANALYSIS. BROADLY, THIS PROPOSAL AIMS TO (1) ANALYTICALLY QUALIFY ACCELEVIRDX'S NOVEL, PROPRIETARY HIFI-DEPCR APPROACH FOR ENV AMPLIFICATION UNDERLYING HIV-1 ENVLRS, (2) DETERMINE THE REPRODUCIBILITY OF THE HIV-1 ENVLRS ASSAY OF SAMPLES FROM PLWH, AND (3) APPLY THE ASSAY TO A RECENTLY COMPLETED ACTG A5340 CLINICAL TRIAL OF THE HIV-1 BNAB VRC01 IN PLWH TO ASSESS ASSAY PERFORMANCE AND UTILITY.