Assessing Susceptibility of Cervical Explant Tissue to HIV-1 Infection Following Masculinizing Hormone Therapy 2250590

Abstract

Abstract Introduction Masculinizing hormonal therapy, integral to gender-affirming care for transgender men (TGM), has immunomodulatory properties that heighten HIV-1 acquisition risk. Testosterone activates immune cells through androgen receptors (ARs), resulting in a cytokine shift and a defective innate immune response. The cervical mucosae are enriched with HIV-1 target cells inclusive of macrophages and CD4+ T cells that co-express ARs. The extent to which this impacts HIV-1 vulnerability in TGM remains unclear. Methods We investigated the impact of hormonal therapy on HIV-1 target cells, in an ex vivo model using cervical tissue explants (CETs). CETs from TGM vs CIS women were sectioned into 2 mm3 blocks for inoculation using Sub A and D T/F IMCs expressing snLuc or msCD24 reporters and monitored over 11 days. HIV-1 infection kinetics were measured using snLuc. HIV-1 infected and uninfected cells were characterized using a 28-color flow cytometry panel and Luminex Results CD4+ T cells were predominantly effector memory in both TGM (95.08% ± 0.54%) and CIS CETs (87.52% ± 0.10%), although CXCR4+CCR5+ co-expression was higher in TGM (28.71% ±0.23%) than CIS (6.79% ± 0.12%; p = 0.0006). The frequency of α4β7+CCR5+CXCR4+CD4Tem (p = 0.0103) and CD38+CD8+ T cells (p = 0.0066) was also higher in TGM. Similar trends were observed, in the TGM “M2” macrophages, although the expression of BST-2 and IFNy was downregulated in TGM. Interestingly, IFNα, CXCL10 and IL-1α, were elevated in TGM compared to CIS CETs culture supernatants. Collectively these findings alluded to increased HIV-1 acquisition risk, as shown by increased HIV-1 replication kinetics in TGM CETs compared to CIS CETs. Conclusion Taken together, our findings suggest increased susceptibility to HIV-1 infection, consistent with testosterone administration. Funding Source UAB Department of Medicine DREAM Council_ Reagan Durant Award Topic Categories Mucosal and Regional Immunology (MUC)