Project Grant R21AI174903

LONGITUDINAL ANALYSIS OF HIV RESERVOIR AND TYPE I/III INTERFERON SYSTEM IN PEOPLE WITH HIV WHO INITIATED ART DURING PRIMARY INFECTION - ABSTRACT EARLY INITIATION OF ANTIRETROVIRAL THERAPY (ART) DURING PRIMARY HIV INFECTION LEADS TO CLEAR PUBLIC HEALTH BENEFITS BY PREVENTING ONWARD HIV TRANSMISSIONS. HOWEVER, IT IS NOT CLEAR HOW THE TIMING OF EARLY ART INITIATION AFFECTS LONGER-TERM INDIVIDUAL OUTCOMES, SUCH AS CHRONIC IMMUNE ACTIVATION. CHRONIC IMMUNE ACTIVATION DURING HIV INFECTION LEADS TO IMMUNE DYSREGULATION AND EXHAUSTION THAT CONTRIBUTES TO DISEASE PROGRESSION AND OTHER CLINICAL PROBLEMS. HEIGHTENED IMMUNE ACTIVATION CONTINUES EVEN AFTER ART SUPPRESSES VIRAL LOADS BELOW THE LIMIT OF DETECTION. OUR GROUP PREVIOUSLY DEMONSTRATED THAT ONE PATHWAY INVOLVED IN IMMUNE ACTIVATION, EXPRESSION OF INTERFERON STIMULATED GENES (ISGS), IS PERSISTENTLY UPREGULATED DURING UNTREATED AND TREATED HIV INFECTION. BUILDING ON THOSE RESULTS, WE HYPOTHESIZE THAT (1) EFFECTIVE ANTIRETROVIRAL TREATMENT DOES NOT COMPLETELY REVERSE CHRONIC ISG ACTIVATION IN PEOPLE LIVING WITH HIV, (2) CHRONIC ACTIVATION OF THE IFN SYSTEM WILL BE LOWER IN PEOPLE WITH HIV (PWH) WHO STARTED ART EARLY, AND (3) HIGHER IFN SYSTEM ACTIVATION CORRELATES WITH A LARGER PROVIRAL RESERVOIR. IDENTIFYING ISG PATHWAYS THAT REMAIN ELEVATED FOLLOWING SEVERAL YEARS OF ART COULD IDENTIFY TARGETS FOR PREVENTING OR TREATING CO-OCCURRING INFLAMMATORY AND DEGENERATIVE DISEASES, WHICH ARE INCREASING IN PREVALENCE AS MORE AND MORE PWH HAVE REMAINED ON ART FOR DECADES. TO EVALUATE THESE HYPOTHESES, WE WILL USE A HIGHLY UNIQUE SET OF ARCHIVED SAMPLES, WITH LONGITUDINAL SAMPLES FROM INDIVIDUALS PRIOR TO HIV INFECTION, DURING PRIMARY INFECTION, AND AFTER TREATMENT INITIATION. THESE SAMPLES COME FROM A STUDY OF EARLY ART INITIATION IN WHICH 1) INDIVIDUALS WITHOUT HIV WERE FOLLOWED MONTHLY WITH SEROLOGY AND RNA TESTING TO DETECT HIV INFECTIONS SHORTLY AFTER ACQUISITION, AND 2) PARTICIPANTS DIAGNOSED WITH HIV WERE RANDOMIZED TO BEGIN ART IMMEDIATELY OR TO DEFER ART FOR 24 WEEKS. THEY WERE FOLLOWED WITH FREQUENT VISITS AND SAMPLE COLLECTIONS FOR UP TO 4 YEARS. IN THE PROPOSED STUDY, WE WILL MEASURE EXPRESSION OF ISGS IN 40 PARTICIPANTS (20 FROM EACH ART ARM) BEFORE HIV INFECTION, AFTER HIV DIAGNOSIS BUT BEFORE ART AND AT 6, 30 AND 48 MONTHS AFTER ART IS STARTED. USING THESE DATA, WE WILL DETERMINE WHETHER ISG EXPRESSION REMAINS ELEVATED AFTER 48 MONTHS OF ART RELATIVE TO PRE-INFECTION SAMPLES FROM THE SAME PARTICIPANT. SECOND, WE WILL EVALUATE IF REDUCTION OF ISG EXPRESSION FOLLOWING ART IS DIFFERENT AMONG THOSE IN THE IMMEDIATE VS. THE DEFERRED ART INITIATION ARMS. LASTLY, WE WILL ASSESS WHETHER ISG ACTIVATION CORRELATES WITH THE SIZE OF THE LATENT HIV RESERVOIR, AS HAS BEEN SUGGESTED BY ANIMAL MODELS BUT REMAINS UNKNOWN IN HUMANS.