Project Grant R43AI165128

IPDA FOR HIGH-PRIORITY HIV-1 SUBTYPE C TO ENABLE GLOBAL ERADICATION TRIALS - 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, HIV-1 INFECTED INDIVIDUALS WILL PROGRESS TO AIDS AND MAY ULTIMATELY DIE AS A RESULT. COMBINATION ANTIRETROVIRAL THERAPY IS EXTREMELY EFFECTIVE AT STOPPING THE REPLICATION OF HIV-1 IN INFECTED INDIVIDUALS. DESPITE THE SUCCESS OF THIS THERAPY 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 A SUBSET OF CD4+ T CELLS KNOWN AS RESTING MEMORY CD4+ T CELLS. IN THIS LATENT STATE, THESE INFECTED CELLS ARE NOT TARGETED BY ANTIRETROVIRAL DRUGS AND CANNOT BE ELIMINATED BY THE IMMUNE SYSTEM. IN HIV-1 INFECTED INDIVIDUALS, LATENTLY INFECTED CD4+ T CELLS ARE FOUND AT EXTREMELY LOW FREQUENCIES (~1 PER MILLION RESTING MEMORY CD4+ T CELLS), WITH THE MAJORITY FOUND WITHIN IMMUNE TISSUES AT ANY GIVEN TIME. THIS POPULATION OF LATENTLY INFECTED CELLS IS VERY STABLE, DEMANDING THAT HIV-1 INFECTED INDIVIDUALS REMAIN ON ANTIRETROVIRAL THERAPY INDEFINITELY TO AVOID REBOUND OF VIREMIA. AS SUCH, THIS POPULATION OF LATENTLY INFECTED CD4+ T CELLS IS THE MAIN BARRIER TO CURING HIV-1 INFECTION. DEVELOPING STRATEGIES TO ELIMINATE LATENTLY INFECTED CELLS IS A MAJOR FOCUS OF THE NIH, NIAID, AND THE HIV-1 RESEARCH FIELD. TO DEMONSTRATE THE EFFICACY OF THERAPEUTICS TARGETING THE LATENT RESERVOIR, WE MUST BE ABLE TO MEASURE THE FREQUENCY OF LATENTLY INFECTED CELLS USING RAPID AND ACCURATE ASSAYS THAT CAN BE SCALED FOR WIDESPREAD CLINICAL USE. CRITICALLY, SUCH ASSAYS MUST BE CAPABLE OF ACCURATELY MEASURING THE SIZE OF THE LATENT RESERVOIR ACROSS VIRAL SUBTYPES. ACCELEVIR DIAGNOSTICS, LLC HAS RECENTLY DEVELOPED THE IPDA AS A NOVEL DIGITAL DROPLET PCR ASSAY TO MEASURE INTACT AND DEFECTIVE PROVIRUSES IN A SMALL SAMPLE OF PERIPHERAL BLOOD. THE IPDA WAS OPTIMIZED FOR USE IN PEOPLE WITH SUBTYPE B HIV-1 INFECTION, WHICH PREDOMINATES IN THE UNITED STATES AND EUROPE BUT COMPRISES ON A SMALL FRACTION OF PEOPLE LIVING WITH HIV-1 WORLDWIDE. IN THIS PROPOSAL, ACCELEVIR DIAGNOSTICS SEEKS TO EXPAND THE IPDA COVERAGE TO INCLUDE PEOPLE LIVING WITH SUBTYPE C HIV-1 INFECTION, WHICH ACCOUNTS FOR APPROXIMATELY 50% OF ALL PEOPLE LIVING WITH HIV-1 WORLDWIDE. BROADLY, THIS PROPOSAL AIMS TO PERFORM IN-DEPTH PROVIRAL SEQUENCING TO INFORM EXPANSION OF ASSAY COVERAGE FOLLOWED BY ASSAY DESIGN ADAPTATION, PERFORMANCE QUALIFICATION, AND ANALYSIS OF LONGITUDINALLY COLLECTED SAMPLES FROM PEOPLE LIVING WITH SUBTYPE C HIV-1 INFECTION. THIS PROPOSAL LEVERAGES A CLOSE COLLABORATION WITH THE US MILITARY HIV RESEARCH PROGRAM, ENABLING ACCESS TO A UNIQUE AND COHORT OF PEOPLE LIVING WITH SUBTYPE C HIV-1 INFECTION ACROSS AFRICA.