Project summary Transgender persons are individuals who were assigned a sex at birth, but experience dysphoria due to their experienced gender not aligning with their assigned sex. One avenue of treatment for gender dysphoria is the use of gender affirming hormone therapy to promote the physical characteristics of the desired sex. This is highly relevant in light of the emerging binary (e.g. male/female) sex-specific differences in HIV vaccine responses, pre-exposure prophylaxis efficacy, viral pathogenesis, and viral reservoir, that may be attributed, at least in part, to sex hormones. Indeed, sex hormone-driven transcriptomic and functional diversity of immune cells within the rectal mucosa (RM) of transgender individuals could have a profound impact on HIV prevention and treatment strategies for theses populations. This is a strong argument for a critical need for basic, foundational research into single-cell transcriptomics and functional assays of RM-residing immune cells, across the gender and sex spectrum. In Aim 1, we will focus on defining the gender- and sex-specific features of adaptive immune cells from cisgender men and women, as well as transgender men and women, via high-resolution, single-cell transcriptomics. In Aim 2, we will define the gender- and sex-specific transcriptomic features of innate immune cells, as well as quantifying gender and sex differences in NK cell function. A more complete understanding of the spectrum of sex-hormone and sex-chromosome influence on the immune system will facilitate strategic HIV prevention and treatment strategies appropriate for transgender individuals.

Public Health Statement A better understanding of the sex-hormone and sex-chromosome mediated immune cell transcriptomic diversity within transgender individuals, as compared to cisgender individuals, could be critical for determining appropriate HIV prevention and treatment strategies for transgender individuals. In this study, we will focus on high- resolution, single-cell analysis of immune cells within the rectal mucosal tissue of cisgender men and women, as well as transgender men and women, to identify new avenues for sex-appropriate HIV interventions.