Ex Vivo Colonic Tissue Susceptibility to HIV-1 in Cisgender Men and Women

The biology of HIV-1 acquisition through unprotected receptive anal intercourse is understudied. Considering that sex hormones are implicated in intestinal physiology, pathology, and HIV acquisition and pathogenesis, we explored links between sex hormones, ex vivo HIV-1_BaL infection of colonic mucosa, and candidate biomarkers of susceptibility to HIV-1 (CD4⁺ T cell frequencies and immune mediators) in cisgender women and men. No consistent significant associations between sex hormone concentrations and ex vivo tissue infection with HIV-1_BaL were detected. In men, serum estradiol (E2) concentrations were positively associated with tissue proinflammatory mediators (IL17A, GM-CSF, IFNγ, TNFα, and MIG/CXCL9) and serum testosterone concentrations were negatively associated with frequencies of activated CD4⁺ T cells (CD4⁺CCR5⁺, CD4⁺HLA-DR⁺, and CD4⁺CD38⁺HLA-DR⁺). In women, the only significant interactions were positive associations between progesterone (P4)/E2 ratios and tissue ILRA concentrations and between P4/E2 ratios and frequencies of tissue CD4⁺α4β7^high+ T cells. The study did not reveal relationships between biological sex or phase of the menstrual cycle and ex vivo tissue HIV-1_BaL infection and tissue immune mediators. A comparison of CD4⁺ T cell frequencies between study groups revealed a higher frequency of tissue CD4⁺α4β7^high+ T cells in women versus men. In contrast, higher frequencies of tissue CD4⁺CD103⁺ T cells were detected in men versus women in the follicular phase of the menstrual cycle. Overall, the study identified associations between systemic sex hormone concentrations, biological sex, and tissue candidate biomarkers of susceptibility to HIV-1. The significance of these results for tissue susceptibility to HIV-1 and early HIV-1 pathogenesis warrants further investigation.