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) 是一种常用的激素避孕药，已被证明可显着增加约 40% 的 HIV-1 易感性。然而，发生这种情况的潜在机制仍然未知。在这里，我们检查了阴道上皮细胞对 MPA 的生物学反应，阴道上皮细胞是性传播过程中遇到 HIV-1 的第一个细胞，以了解 MPA 介导的 HIV-1 感染增加的潜在机制。使用微阵列分析和体外在分析中，我们表征了在生物学相关的气液界面 (ALI) 培养物中生长的阴道上皮细胞对雌性激素、雌二醇 (E2)、孕酮 (P4) 或 MPA 的生理水平的反应。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/甾醇合成相关的基因转录本，并减少了与细胞分裂和细胞-细胞粘附相关的转录本，E2 或 P4 处理未见结果。MPA 处理还导致独特的基因表达，表明屏障完整性降低。功能分析证实，MPA（而非 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。