Project Summary/Abstract Despite a disproportionately high burden of HIV infection among transgender women and transgender men in the US, gender minorities remain underrepresented in HIV prevention research. While many transgender individuals utilize feminizing and masculinizing hormones, there are critical knowledge gaps in our mechanistic understanding of the effects of gender-affirming hormone therapy on the rectal mucosal environment, a critical site of vulnerability to HIV infection. This is of paramount importance, as biological sex and sex hormones mediate effects on epithelial and immune cell function through their influence on transcriptional activity of the cell, and these effects could alter the susceptibility of the rectal mucosa to HIV infection. The Specific Aims of this proposal are to compare sex-specific, spatially localized gene expression patterns of rectal mucosal immune and epithelial cell subpopulations between cisgender men and cisgender women utilizing spatial transcriptomics integrated with single cell RNA sequencing (Aim 1), to define the single cell transcriptomic signatures of rectal mucosal cellular subsets from cisgender men and cisgender women following ex vivo sex hormone exposure (Aim 2), and to use the HIV explant challenge model to examine the impact of ex vivo sex hormone treatment on rectal tissue susceptibility and host mucosal immune responses to HIV infection (Aim 3). This research strategy will facilitate a 5-year career development and training plan that will enable Dr. Grimsley Ackerley to build upon her prior research experience and gain critical mentored research training in: 1) Bioinformatics and Transcriptomic Data Analyses, 2) Mucosal Immunology and HIV transmission, and 3) the Conduct of Sex- and Gender-Based HIV Research. To achieve these training aims, Dr. Grimsley Ackerley has assembled a multidisciplinary mentorship team with expertise in mucosal immunology, sex hormone biology, single cell and spatial transcriptomic technologies, sex- and gender-based research, and biostatistics. This proposal will capitalize on a robust research environment at Emory University and will be supported by resources available through The Hope Clinic of the Emory Vaccine Center and the Emory National Primate Research Center. Dr. Grimsley Ackerley’s long-term career goal is to lead a successful and independent translational mucosal immunology program that specializes in the use of genomics applications and the ex vivo HIV explant challenge model to better understand biologic and immunologic factors that influence mucosal HIV susceptibility among gender and sexual minority populations. Achievement of this long-term goal will be made possible through the completion of the proposed K23 research aims and training plan, along with the support garnered from the highly experienced mentorship team. This proposal will begin to address, mechanistically, the effects of biological sex and gender-affirming hormone therapy on the rectal mucosal environment and rectal HIV susceptibility. The data generated will serve as the foundation for future NIH R-level funding to facilitate Dr. Grimsley Ackerley’s transition to an independent clinical-translational research career in the field of HIV prevention science.

Project Narrative Many transgender people have an increased risk of HIV acquisition compared to the general population, yet little is known about how the use of gender-affirming hormones may impact mucosal HIV transmission. In this proposal, we will examine the effects of biological sex and sex hormone treatment on rectal mucosal epithelial and immune cell transcriptomic diversity and function, and we will assess the impact of sex hormone treatment on rectal mucosal immune responses and HIV susceptibility. A better understanding of rectal HIV transmission among transgender people utilizing gender-affirming hormone therapy could contribute to the development of sex- and gender-specific biomedical HIV prevention interventions.