Project Grant R01AI181701

MODULATING INDOLEAMINES TO OPTIMIZE IMMUNITY IN THE SETTING OF MTB/HIV CO-INFECTION - PROJECT SUMMARY TB REMAINS THE LEADING CAUSE OF DEATH IN HIV-INFECTED PERSONS, WITH ONE IN FOUR DEATHS ATTRIBUTABLE TO TB. WHILE THE MAJORITY OF HEALTHY INDIVIDUALS INFECTED WITH MYCOBACTERIUM TUBERCULOSIS (MTB) CONTROL INFECTION, CO-INFECTION WITH HIV INCREASES THE RISK OF PROGRESSING TO TB DISEASE BY OVER 20 FOLD. ANTIRETROVIRAL THERAPY (ART) DECREASES THE INCIDENCE OF ATB AND REMAINS THE CORNERSTONE OF HIV CARE. HOWEVER, THE INCIDENCE OF TB IN HIV-CO-INFECTED INDIVIDUALS REMAINS FOUR-TO-SEVEN-FOLD HIGHER AFTER ART THAN IN HIV-UNINFECTED PEOPLE IN TB-ENDEMIC SETTINGS, REGARDLESS OF THE DURATION OF ART OR ATTAINMENT OF HIGH CD4+ T CELL COUNTS. WE HAVE DEVELOPED MACAQUE MODELS OF MTB/HIV CO-INFECTION WHICH UTILIZE ART. DEPENDING ON THE TIMING OF ART-INTERVENTION, SIV REPLICATION IN THE PERIPHERY AS WELL AS TISSUES IS EITHER EFFECTIVELY INHIBITED OR NOT, RECAPITULATING THE WHOLE SPECTRUM OF HUMAN TISSUE-SPECIFIC AND CLINICAL OUTCOMES. THIS ALLOWS FOR DETAILED LONGITUDINAL AND MECHANISTIC STUDIES THAT ARE NOT POSSIBLE IN HUMANS. OUR DATA SHOWS A CLEAR ROLE FOR INDOLE 2,3, DIOXYGENASE (IDO) IN BOTH THE INHIBITION OF EFFECTIVE IMMUNITY TO TB AS WELL AS IN ORCHESTRATING CHRONIC IMMUNE ACTIVATION IN SIV-INFECTED MACAQUES. BLOCKADE OF IDO PATHWAY IMPROVES THE OUTCOME OF TB AND HIV IN SINGLY INFECTED MACAQUES. HERE, WE WILL USE INHIBITION APPROACHES IN THE RM MODELS OF MTB/SIV/ART TO TEST THE HYPOTHESIS THAT THIS WILL IMPROVE ANTI-TB IMMUNE RESPONSES, INHIBIT HIV-INDUCED CHRONIC IMMUNE ACTIVATION, THUS ALLOWING THE IMMUNE SYSTEM TO BETTER CONTROL THE CO-INFECTION. OUR PROPOSED STUDIES WILL PROVIDE UNPRECEDENTED NOVEL INSIGHTS INTO THE MOLECULAR MECHANISMS THAT MEDIATE REACTIVATION OF TB IN THE SETTING OF HIV INFECTION, AND IDENTIFY PROTECTIVE IMMUNE MECHANISMS THAT WILL INFORM THE DEVELOPMENT OF NEW TREATMENT REGIMENS AND VACCINES FOR TB.