Project Grant F30DK149860

MICROBIAL REGULATION OF HIV PERSISTENCE IN THE GUT - PROJECT SUMMARY/ABSTRACT. ALTHOUGH ANTIRETROVIRAL THERAPY (ART) EFFECTIVELY SUPPRESSES HIV REPLICATION, IT DOES NOT ELIMINATE A LONG-LIVED RESERVOIR OF HIV-INFECTED CELLS THAT CAN REIGNITE VIREMIA WHEN THERAPY IS INTERRUPTED. THE LARGEST RESERVOIR OF THESE CELLS RESIDES IN THE GUT, WHICH IS A UNIQUE ENVIRONMENT SHAPED BY CONSTANT EXPOSURE TO MICROBIAL ANTIGENS AND MICROBIOME-DERIVED METABOLITES. GROWING EVIDENCE DEMONSTRATES THAT GUT MICROBIOME COMPOSITIONS AND MICROBIAL METABOLITES CORRELATE WITH HIV RESERVOIR SIZE, YET THE MECHANISMS BY WHICH GUT ANTIGENIC AND METABOLIC SIGNALS SUSTAIN AND IMPACT THE HIV RESERVOIR REMAIN UNKNOWN. THIS PROJECT INVESTIGATES HOW MICROBIAL ANTIGENS AND METABOLITES REGULATE THE PERSISTENCE AND TRANSCRIPTIONAL ACTIVITY OF THE ACTIVE HIV RESERVOIR. AIM 1 WILL DEFINE THE ANTIGENIC LANDSCAPE OF ACTIVE RESERVOIR CELLS BY INTEGRATING HIV-SEQ, SINGLE-CELL TRANSCRIPTOMICS, SURFACE PHENOTYPING, AND TCR SEQUENCING OF CD4+ T CELLS DERIVED FROM GUT BIOPSIES (ILEUM AND COLON) OF ART- SUPPRESSED PEOPLE LIVING WITH HIV (PLWH). ANTIGEN SPECIFICITY WILL BE ASSIGNED USING VDJDB AND VIRAFEST TO COMPARE THE TRANSCRIPTIONAL PROFILES AND ANTIGEN-INDUCED RESPONSES BETWEEN MICROBIOME-SPECIFIC AND VIRAL- SPECIFIC RESERVOIR CELLS. AIM 2 WILL IDENTIFY MICROBIOME-DERIVED METABOLITES ASSOCIATED WITH HIV TRANSCRIPTIONAL ACTIVITY USING UNTARGETED STOOL METABOLOMICS AND THEN TEST THEIR EFFECTS IN HIV LATENCY MODELS. PARALLEL EXPERIMENTS USING STOOL-DERIVED STERILE FECAL WATER WILL ASSESS WHETHER THESE EFFECTS PERSIST WITHIN THE COMPLEX MIXTURE OF METABOLITES DERIVED FROM THE STOOL OF PLWH. TOGETHER, THESE STUDIES WILL REVEAL ANTIGENIC AND METABOLIC PATHWAYS THAT MAY IMPACT HIV PERSISTENCE AND POTENTIALLY UNCOVER NEW MICROBIOME-LINKED TARGETS TO DESTABILIZE THE ACTIVE RESERVOIR. THE PROPOSED STUDIES ARE HIGHLY RELEVANT TO RESEARCH PRIORITIES IN GUT PHYSIOLOGY, MICROBIOME-HOST INTERACTIONS, AND METABOLIC PATHWAYS THAT INFLUENCE CHRONIC DISEASE. BY DEFINING GUT-MEDIATED ANTIGENIC AND METABOLIC MECHANISMS THAT MAINTAIN THE ACTIVE HIV RESERVOIR DURING ART, THIS WORK ADVANCES MECHANISTIC INSIGHT INTO HOW THE GUT ENVIRONMENT SHAPES PERSISTENT VIRAL INFECTION. THIS FELLOWSHIP TRAINING PLAN INTEGRATES FOUR COMPLEMENTARY GOALS: ADVANCED TRAINING IN HIV IMMUNOLOGY, MULTI-OMICS, AND MICROBIOME DATA ANALYSIS; DEVELOPMENT OF TRANSFERABLE SCIENCE SKILLS IN COMMUNICATION, HYPOTHESIS GENERATION, AND MENTORSHIP THROUGH WORKSHOPS AND CO-SPONSOR GUIDANCE; CLINICAL SKILL-BUILDING THROUGH PRECEPTORSHIPS; AND STRENGTHENED INTEGRATION OF CLINICAL AND SCIENTIFIC PERSPECTIVE THROUGH MEETINGS WITH PHYSICIAN-SCIENTIST MENTORS AND PARTICIPATION IN CLINICAL CASE REVIEWS. RESEARCH WILL OCCUR AT THE GLADSTONE INSTITUTES, WHICH OFFERS EXCEPTIONAL RESEARCH INFRASTRUCTURE, INCLUDING ADVANCED CORE FACILITIES, WELL-MAINTAINED EQUIPMENT, AND A COLLABORATIVE ENVIRONMENT WITH HIGHLY ACCESSIBLE TECHNICAL EXPERTS. ITS INTEGRATION WITHIN THE UCSF CAMPUS ENSURES CONVENIENT ACCESS, BY FOOT OR FREE SHUTTLE, TO A WIDE ARRAY OF SHARED RESOURCES THAT WILL DIRECTLY FACILITATE THE SUCCESSFUL COMPLETION OF THIS PROJECT. THIS PROJECT WILL ALSO BE GUIDED BY AN INTERDISCIPLINARY AND HIGHLY ENGAGED MENTORSHIP TEAM AND SUPPORTED BY ACCESS TO WELL-CHARACTERIZED HIV CLINICAL COHORTS BASED AT UCSF.