Project Grant R21AI179004

UNDERSTANDING THE EFFECTS OF GENDER AFFIRMING HORMONE THERAPY (GAHT) ON IMMUNE FUNCTION USING A SYSTEMS IMMUNOLOGY APPROACH - PROJECT SUMMARY ONE MILLION INDIVIDUALS IN THE UNITED STATES IDENTIFY AS TRANSGENDER (0.39% OF POPULATION), OF WHICH 90% ARE EITHER ON GENDER-AFFIRMING HORMONE THERAPY (GAHT) OR CONSIDERING STARTING GAHT. UNDERSTANDING HOW FEMINIZING GAHT (ESTRADIOL) AND MASCULINIZING GAHT (TESTOSTERONE) INFLUENCE IMMUNE FUNCTION IS IMPERATIVE, CONSIDERING THAT (I) TRANSGENDER WOMEN HAVE A SIGNIFICANTLY INCREASED PREVALENCE OF HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION WORLDWIDE AND (II) LITTLE IS KNOWN ABOUT HOW GAHT INFLUENCES IMMUNE FUNCTION OR SUSCEPTIBILITY TO INFECTIONS. TO ADDRESS THIS GAP IN KNOWLEDGE, OUR TEAM WILL COMBINE ESTABLISHED STATE-OF-THE-ART SYSTEMS IMMUNOLOGY APPROACHES TO A COMPLETED LONGITUDINAL COHORT OF TRANSGENDER WOMEN BEFORE AND DURING GAHT. WE PREVIOUSLY USED THIS LONGITUDINAL MODEL TO SHOW THAT BOTH FEMINIZING AND MASCULINIZING GAHT INDUCED DNA METHYLATION CHANGES AT SPECIFIC GENOMIC LOCI IN WHOLE PERIPHERAL BLOOD, SOME OF WHICH WERE PREVIOUSLY ASSOCIATED WITH PUBERTY OR PREGNANCY. IN THE FIRST THREE AIMS OF THIS PROJECT, WE WILL USE VIABLY STORED PERIPHERAL BLOOD MONONUCLEAR CELLS FROM TRANSGENDER WOMEN AT BASELINE, AND 3 AND 6 MONTHS FOLLOWING GAHT. BY APPLYING A SYSTEMS IMMUNOLOGY APPROACH, WE FIRST SEEK TO ESTABLISH HOW GAHT CHANGES THE CIRCULATING IMMUNE PROFILE AND PLASMA METABOLITES, BOTH OF WHICH ARE PREDICTORS OF RESPONSE TO INFECTION AND VACCINES. NEXT, INNATE, AND ADAPTIVE IMMUNE FUNCTION WILL BE ASSESSED THROUGH IN VITRO STIMULATION WITH A RANGE OF MICROBIAL AND VIRAL MICROBES, SPECIFICALLY HIV, FOLLOWED BY CYTOKINE ASSAYS. FINALLY, IN AIM 3 WE WILL MAP THE UNDERLYING EPIGENOMIC PROFILE OF SPECIFIC IMMUNE CELL TYPES, BY PROFILING ACTIVE HISTONE MODIFICATIONS AND OPEN CHROMATIN AT SINGLE CELL LEVEL. TOGETHER, THE ABOVE APPROACH WILL IDENTIFY THE KEY MOLECULAR DRIVERS OF ALTERED IMMUNE FUNCTION IN RESPONSE TO GAHT AND GENERATE NEW HYPOTHESES FOR FURTHER STUDY. ULTIMATELY, UNDERSTANDING HOW GAHT ALTERS THE MOLECULAR BIOLOGY OF IMMUNE CELLS WILL OPEN NEW AVENUES TO THERAPEUTIC INTERVENTION IN CASES WHERE IMMUNE FUNCTION IS COMPROMISED BECAUSE OF GAHT. IN AIM 4, WE WILL USE OUR ESTABLISHED LONGITUDINAL GAHT RECRUITMENT STRATEGY TO ESTABLISH A COHORT OF TRANSGENDER INDIVIDUALS WITH EXTENSIVE BIOSPECIMEN COLLECTION. THIS WILL ALLOW US TO EXPLORE THE EFFECTS OF GAHT ON THE VAGINAL AND FECAL MICROBIOTA AND STRESS, WHICH ARE KNOWN MODULATORS OF IMMUNITY. ONCE ESTABLISHED, THIS LONGITUDINAL COHORT WILL PROVIDE OPPORTUNITIES TO APPLY A RANGE OF STATE-OF-THE-ART MOLECULAR AND IMMUNOPHENOTYPING TECHNIQUES TO UNDERSTAND IF AND HOW GAHT AFFECTS SUSCEPTIBILITY TO HIV INFECTION.