Project Grant R24AI143502

CENTRALIZED RESOURCE TO ACCURATELY QUANTIFY LATENT AND EXPRESSED HIVRESERVOIRS - 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 IN BOTH PERIPHERAL BLOOD AND IMMUNE TISSUES. ACCELEVIR DIAGNOSTICS, LLC THEREFORE DEVELOPED, SCALED, AND IS CURRENTLY OPERATING AN NIAID RESOURCE TO PERFORM AN ARRAY OF INNOVATIVE MOLECULAR AND GENOMIC ASSAYS TO ACCURATELY MEASURE THE SIZE OF THE LATENT RESERVOIR, THE AMOUNT OF RESIDUAL VIREMIA PRESENT IN THE PERIPHERAL BLOOD, AND THE TRANSCRIPTIONAL ACTIVITY OF PERSISTENT PROVIRUSES TO SUPPORT RESEARCH, PRECLINICAL, AND CLINICAL STUDIES. THIS RESOURCE HAS ALREADY SUPPORTED OVER 100 PROJECTS ACROSS THE HIV-1 CURE RESEARCH FIELD, PRODUCING OVER 10,000 TEST RESULTS. BROADLY, THIS RENEWAL PROPOSAL WILL FUND THE CONTINUED OPERATION OF THIS IMPORTANT RESOURCE AND EXPAND THE MENU OF VIRAL PERSISTENCE ASSAYS OFFERED TO SUPPORT GLOBAL RESEARCH EFFORTS.