Project Grant R01AG094488

THE NEXUS OF TRAINED IMMUNITY AND STABLE IMMUNE COMPLEXES: IMPLICATIONS FOR AGING-RELATED CONDITIONS IN PLWH - PROJECT SUMMARY APPROXIMATELY 38.4 MILLION PEOPLE ARE LIVING WITH HIV GLOBALLY, AND THERE ARE STILL NEW INFECTIONS DAILY. PEOPLE LIVING WITH HIV ON ANTIRETROVIRAL THERAPY ARE AGING AT A FASTER RATE THAN THEIR PEERS. THIS IS LIKELY DRIVEN BY THE HIV RESERVOIR THAT PERSISTS EVEN IN AVIREMIC PATIENTS. THE HIV RESERVOIR AND OTHER CO-INFECTIONS, SUCH AS CYTOMEGALOVIRUS (CMV), PROMOTE CHRONIC INFLAMMATION, WHICH FURTHER CONTRIBUTES TO ACCELERATED AGING. OUR OVERARCHING HYPOTHESIS IS THAT CHRONIC INFLAMMATION ACCELERATES AGING-RELATED DISEASES SUCH AS DIABETES, CARDIOVASCULAR DISEASE, AND CANCER IN PEOPLE LIVING WITH HIV, EVEN IN THE ABSENCE OF DETECTABLE VIRAL LOAD. IN PREVIOUS STUDIES, OUR GROUP DEMONSTRATED THAT PEOPLE LIVING WITH HIV EXHIBIT A SIGNIFICANT INCREASE IN CMV- SPECIFIC CD4+ T CELLS, A PHENOMENON DESCRIBED AS 'INFLATION.' THIS INFLATION IS UNIQUE TO HIV, AS SIMILAR INCREASES HAVE NOT BEEN OBSERVED IN STUDIES OF IMMUNE SUPPRESSION IN TRANSPLANT PATIENTS, SUGGESTING AN INTERACTION BETWEEN HIV AND CMV. BEYOND THIS, PEOPLE LIVING WITH HIV WITH METABOLIC DISEASE HAVE INCREASED PROPORTIONS OF CIRCULATING IMMUNE COMPLEXES (CD3+ T CELL CD14+ MONOCYTES). TRADITIONALLY, THESE COMPLEXES HAVE BEEN DISMISSED AS ARTIFACTS. HOWEVER, STUDIES SUGGEST THAT THESE ARE FUNCTIONAL COMPLEXES. IN PEOPLE WITH HIV, THESE COMPLEXES ARE ACTIVATED, INVERSELY CORRELATED WITH CD4+ REGULATORY T CELLS AND PLASMA INTERLEUKIN (IL)-10 LEVELS AND CONTAIN REPLICATING HIV. THESE FINDINGS HIGHLIGHT THE ROLE OF THESE COMPLEXES IN HIV AND METABOLIC DISEASES. GIVEN THEIR FUNCTIONAL NATURE, CD3+ T CELL CD14+ MONOCYTE COMPLEXES PROVIDE A UNIQUE OPPORTUNITY TO DEFINE THE ANTIGEN DRIVERS IN DIABETES, CARDIOVASCULAR DISEASE, AND AGING TO DEVELOP TARGETED IMMUNE INTERVENTIONS WITH FEWER ADVERSE EFFECTS. THIS PROPOSAL WILL LEVERAGE THE CENTER FOR AIDS RESEARCH NETWORK OF INTEGRATED CLINICAL SYSTEMS (CNICS), A LONGITUDINAL COHORT OF PATIENTS WITH ADJUDICATED OUTCOMES ACROSS MULTIPLE SITES, TO STUDY THE IMMUNE COMPLEXES OVER TIME. WE PROPOSE THREE AIMS. IN THE FIRST AIM, WE WILL INVESTIGATE WHETHER IMMUNE COMPLEXES ARE ELEVATED IN PEOPLE LIVING WITH HIV WHO ALSO HAVE CARDIOVASCULAR DISEASE OR CANCER. THIS APPROACH WILL ENABLE US TO DETERMINE WHETHER THE IMMUNE COMPLEXES IN THESE INDIVIDUALS DIFFER FUNCTIONALLY FROM THOSE FOUND IN PEOPLE LIVING WITH HIV AND DIABETES. IN THE SECOND AIM, WE WILL TEST THE HYPOTHESIS THAT BOTH HOST-DERIVED FACTORS, SUCH AS MAJOR HISTOCOMPATIBILITY COMPLEXES, AND NON- HOST-DERIVED FACTORS, INCLUDING SMOKING, METABOLITES, AND LIPIDS, PROMOTE THE FORMATION AND PERSISTENCE OF IMMUNE COMPLEXES. FINALLY, THE THIRD AIM WILL EXAMINE WHETHER CD3+ T CELLS WITHIN THESE COMPLEXES INDUCE EPIGENETIC CHANGES IN CD14+ MONOCYTES, LEADING TO PATHOGENIC TRAINED IMMUNITY. WE SEEK TO IDENTIFY MECHANISMS DRIVING AGING IN PEOPLE LIVING WITH HIV, ULTIMATELY PAVING THE WAY FOR TARGETED THERAPIES THAT COULD SLOW DOWN AGING AND REDUCE COMORBIDITIES IN THIS POPULATION. OUR FINDINGS WILL INFORM THE DEVELOPMENT OF TARGETED ANTI-INFLAMMATORY THERAPIES, POTENTIALLY TRANSFORMING THE MANAGEMENT OF AGING-RELATED COMORBIDITIES.