Effects of Injectable DMPA and Combined Oral Contraceptive Use on HIV Susceptibility Factors in Pig-tailed Macaques

Progestin-based contraception may increase the risk of vaginal HIV acquisition to a level greater than the progesterone-rich luteal phase of the menstrual cycle, which has been demonstrated to have a significantly higher transmission rate compared to the follicular phase. We used pig-tailed macaque (Macaca nemestrina) model to evaluate the effects of administration of the oral the combined oral contraceptives (COCs) depot medroxyprogesterone acetate (DMPA) and levonorgestrel (LNG) on mucosal factors that influence HIV susceptibility. We compared the pH and vaginal epithelial thickness data from previous studies, and evaluated contraception-induced molecular changes in the vagina using transcriptional and cytokine profiling. The administration of DMPA caused a pronounced thinning of the vaginal epilthelium relative to measurements takein in the follicular or luteal phase. DMPA also induced a significant increase in vaginal IL10 expression. Lastly, using RNA-Seq analyses of vaginal biopsies, we noted that both DMPA- and LNG-based contraception induced a signature of gene expression similar to that of the luteal phase, only more exacerbated, and including widespread down-regulation of HIV-restriction genes. Use of progestin-based contraception might engender a milieu that poses an increased risk of HIV transmission than that of the luteal phase via vaginal thinning, induction of immunosuppressive cytokines, and widespread suppression of HIV restriction factors. 15 animals were divided into 4 sub-phases of the menstrual cycle. Vaginal pinch biopsy samples from pre-treatment (baseline) and post-HC (COC, 5 weeks after first dose; DMPA, 2 weeks post-second injection) were hybridized to Affymetrix GeneChip® Rhesus Macaque Genome Arrays.

以孕激素为基础的避孕方法可能会使阴道HIV感染风险升高至高于月经周期中孕激素丰富的黄体期的水平——已有研究证实，黄体期的HIV传播率显著高于卵泡期。本研究采用豚尾猴（Macaca nemestrina）模型，评估复方口服避孕药（combined oral contraceptives, COCs）、醋酸甲羟孕酮长效注射剂（depot medroxyprogesterone acetate, DMPA）及左炔诺孕酮（levonorgestrel, LNG）给药后，对影响HIV易感性的黏膜因子的调控作用。研究人员对比了既往研究中的阴道pH值与阴道上皮厚度数据，并通过转录组和细胞因子谱分析，评估了避孕药物诱导的阴道分子变化。相较于卵泡期或黄体期的测量结果，醋酸甲羟孕酮长效注射剂（DMPA）给药可导致阴道上皮显著变薄；同时，DMPA还可诱导阴道白细胞介素10（IL-10）表达显著升高。最后，通过阴道活检组织的RNA测序（RNA-Seq）分析，研究团队发现，基于DMPA与LNG的避孕方法均可诱导出与黄体期相似的基因表达特征，且该效应更为显著，其中包括HIV限制基因的广泛下调。基于孕激素的避孕方法可能通过阴道上皮变薄、诱导免疫抑制性细胞因子产生，以及广泛抑制HIV限制因子，构建出比黄体期更高危的HIV传播微环境。本研究共纳入15只动物，将其分为月经周期的4个亚阶段。分别在预处理（基线）及激素避孕（HC）给药后（复方口服避孕药组为首次给药后5周；DMPA组为第二次注射后2周）采集阴道钳夹活检样本，将其与Affymetrix GeneChip® 恒河猴基因组基因芯片进行杂交。