Short Communication:Transgender Women on Feminizing Hormone Therapy Demonstrate a Distinct Rectal Mucosal Transcriptome from Cisgender Men.

Among transgender women (TGW), the effects of feminizing hormone therapy use on rectal mucosal (RM) HIV transmission are largely unknown. In this small pilot study, we compared the RM transcriptome in TGW utilizing feminizing hormone therapy with a group of cisgender men who have sex with men (MSM) engaging in condomless receptive anal intercourse (AI) and to a group of cisgender men who had never engaged in AI. There were 498 differentially expressed genes (DEGs) in TGW compared with men who had never engaged in AI, and 154 DEGs compared with the MSM. Among TGW, a unique RM transcriptome was identified that implicated pathways critical for mucosal immune responses, including upregulation of genes that mediate immune cell activation and the production of cytokines and other immune signaling molecules. Furthermore, gene set enrichment analyses identified immune signatures that implicated enrichment of proinflammatory immunological pathways in TGW, specifically involving interferon-α, interleukin-6, and tumor necrosis factor-α signaling, whereas metabolic pathways were shown to be enriched among the cisgender male groups. These findings suggest that TGW have a distinct RM immune environment influenced by the use of feminizing hormones, and consequently, there is an urgent need for further investigation into the immunological effects of gender-affirming hormone therapy and its potential impact on HIV mucosal transmission risk for transgender individuals.