Shreya Joshi, McMaster University

Shreya Joshi, Aisha Nazli and Charu Kaushic (McMaster Immunology Research Centre, Department of Medicine, McMaster University, Hamilton, ON, Canada, L8S 4L8)

Suppressing & Conquering

HIV disproportionately affects women, with about 45% of infections occurring in the female reproductive tract. Our lab and others have demonstrated that sex hormones have a significant effect on HIV susceptibility. In general, while estrogen (E2) confers protection, progesterone (P4) increases HIV susceptibility. However, the underlying mechanisms remain unclear. MicroRNAs-small non-coding regulators of gene expression are modulated by hormones as well and can influence disease outcomes. Here, we investigated how sex hormones modulate HIV susceptibility through differential microRNA expression in vaginal epithelial cells (VK2). Physiological concentrations of E2 (10^-9-10^-10M) and P4 (10^-7-10^-8M) were tested to determine optimal levels that alter microRNA expression. In separate experiments, VK2 cells were exposed to HIV-1 (30 mins to 24 hours), to assess its impact on microRNAs. Based on preliminary data, high-throughput microRNA sequencing was performed on VK2 cells grown in E2 (10^-9M) or P4 (10^-7M) and exposed to HIV for 8 hours, to identify differentially expressed (DE) microRNAs. E2, P4 and HIV altered 42, 117 and 31 distinct microRNAs, respectively. Co-treatment with E2-HIV modulated 31 and P4-HIV altered 37 distinct microRNAs. Pathway analysis revealed that E2-DE microRNAs regulate pathways associated with proliferation and epithelial barrier integrity, including mTOR signaling, adherens junction and focal adhesion. P4-DE microRNAs regulate cell cycle and p53 signaling while HIV-DE microRNAs regulate MAPK, cytokine and TGF-β signaling, affecting innate immune response. Functional role of these microRNAs will be validated using microRNA inhibitors. These findings indicate that microRNAs may mediate hormone-driven differential HIV susceptibility, making them potential therapeutic targets against HIV.