Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote Center for Learning and Discovery, Hamilton, Ontario, L8P 3Z5, Canada; McMaster Immunology Research Center, McMaster University, Michael G. DeGroote Center for Learning and Discovery, Hamilton, Ontario, L8S 4L8, Canada.
Health Sciences North Research Institute, Sudbury, ON, P3E 5J1, Canada.
J Reprod Immunol. 2021 Feb;143:103253. doi: 10.1016/j.jri.2020.103253. Epub 2020 Dec 1.
Medroxyprogesterone acetate (MPA) is a frequently used hormonal contraceptive that has been shown to significantly increase HIV-1 susceptibility by approximately 40 %. However, the underlying mechanism by which this occurs remains unknown. Here, we examined the biological response to MPA by vaginal epithelial cells, the first cells to encounter HIV-1 during sexual transmission, in order to understand the potential mechanism(s) of MPA-mediated increase of HIV-1 infection. Using microarray analysis and in vitro assays, we characterized the response of vaginal epithelial cells, grown in biologically relevant air-liquid interface (ALI) cultures, to physiological levels of female sex hormones, estradiol (E2), progesterone (P4), or MPA. Transcriptional profiling of E2, P4 or MPA-treated vaginal epithelial cells indicated unique transcriptional profiles associated with each hormone. MPA treatment increased transcripts of genes related to cholesterol/sterol synthesis and decreased transcripts related to cell division and cell-cell adhesion, results not seen with E2 or P4 treatments. MPA treatment also resulted in unique gene expression indicative of decreased barrier integrity. Functional assays confirmed that MPA, but not E2 or P4 treatments, resulted in increased epithelial barrier permeability and inhibited cell cycle progression. The effects of MPA on vaginal epithelial cells seen in this study may help explain the increase of HIV-1 infection in women who use MPA as a hormonal contraceptive.
醋酸甲羟孕酮（MPA）是一种常用的激素类避孕药，已被证明可使 HIV-1 易感性增加约 40%。然而，其发生的潜在机制仍不清楚。在这里，我们通过阴道上皮细胞（性传播过程中首先遇到 HIV-1 的细胞）来检查 MPA 的生物学反应，以了解 MPA 介导的 HIV-1 感染增加的潜在机制。我们使用微阵列分析和体外检测，对在具有生物学相关性的气液界面（ALI）培养物中生长的阴道上皮细胞对女性性激素雌二醇（E2）、孕酮（P4）或 MPA 的生理水平的反应进行了表征。E2、P4 或 MPA 处理的阴道上皮细胞的转录谱表明，与每种激素相关的独特转录谱。MPA 处理增加了与胆固醇/固醇合成相关的基因的转录物，减少了与细胞分裂和细胞-细胞黏附相关的转录物，这与 E2 或 P4 处理不同。MPA 处理还导致独特的基因表达，表明屏障完整性降低。功能检测证实，只有 MPA 处理而不是 E2 或 P4 处理导致上皮屏障通透性增加，并抑制细胞周期进程。本研究中观察到的 MPA 对阴道上皮细胞的影响可能有助于解释使用 MPA 作为激素避孕药的女性中 HIV-1 感染增加的原因。
