Prevention of HIV transmission/acquisition through informed contraceptive choice

描述(由申请人提供)：尽管其可获得性、可负担性和有效性，但人们担心，去甲羟孕酮(DEPO-MPA，DMPA)会增加妇女对艾滋病毒-1的易感性。因此，我们寻求对避孕孕激素对HIV-1传播的影响的更好的了解。避孕类固醇的作用高度依赖于受体结合和局部浓度，猕猴研究表明了内孕病毒在SIV传播中的重要性。尽管如此，在使用这些药物的女性中，没有任何避孕孕激素的局部宫颈内浓度的数据。系统递送的DMPA预计会产生较低的生殖道浓度的MPA。MPA对糖皮质激素受体(GR)的强烈亲和力可能使其能够调节免疫和物理上皮屏障功能，从而促进艾滋病毒在宫颈内的传播。作为DMPA的替代品，左炔诺孕酮(LNG)、诺美孕酮醋酸酯(NOMAC)和PR调节剂ulipristal(UL)对GR的亲和力很差，可能会以较高的局部浓度被释放到生殖道。我们假设，与低水平的MPA不同，高水平的LNG、NOMAC或UL保护子宫内膜的物理和固有上皮屏障，并减少该部位的HIV-1传播。我们将使用DMPA、释放LNG的宫内节育器和含孕酮的阴道环来测量妇女宫颈内的孕激素水平，并评估孕激素类型和投放方式对宫颈粘液对HIV-1的物理和免疫屏障的影响。接下来，我们将把两极分化的激素敏感的宫颈内皮细胞暴露在生理水平的避孕孕激素中，并跟踪单层完整性、先天免疫反应和艾滋病毒-1跨越这一屏障传播的变化。最后，我们将研究使用DMPA和LNG-IUD的妇女宫颈内T细胞对HIV-1的敏感性，并检验在低水平的MPA而不是高水平的LNG、NOMAC或UL的情况下，上皮介质增加T细胞对HIV-1的敏感性的假设。了解使用DMPA的妇女中艾滋病毒-1传播增加的机制，以及替代孕激素和分娩方法对传播事件的不同影响，将使人们能够知情地建议对高危妇女使用最安全的避孕方法。

DESCRIPTION (provided by applicant): Despite its availability, affordability and efficacy, there is a concern that depo medroxyprogesterone acetate (depo-MPA, DMPA) increases the susceptibility of women to HIV-1. Accordingly, we seek an improved knowledge of the effects of contraceptive progestins on HIV-1 transmission. Contraceptive steroid effects are highly dependent on receptor-binding and local concentration and macaque studies illustrate the importance of the endocervix in SIV transmission. Still, there are no data on local endocervical concentrations of any contraceptive progestins in women using these medications. Systemically-delivered DMPA is predicted to produce low genital tract concentrations of MPA. MPA's strong affinity for the glucocorticoid receptor (GR) may enable it to modulate immune and physical epithelial barrier functions that promote HIV transmission in the endocervix. As alternatives to DMPA, levonorgestrel (LNG), nomegestrel acetate (NOMAC) and the PR modulator, ulipristal (UL), have poor affinity for the GR and may be delivered in high local concentrations to the genital tract. We hypothesize that high levels of LNG, NOMAC or UL, unlike low levels of MPA, protect the physical and innate epithelial barrier of the endocervix and decrease HIV-1 transmission at this site. We will measure progestin levels in the endocervix of women using DMPA, an LNG-releasing IUD and a progestin-containing vaginal ring and assess effects of progestin type and delivery method on the physical and immune barrier of cervical mucus to HIV-1. Next, we will expose polarized, hormone-responsive endocervical epithelial cells to physiologic levels of contraceptive progestins and follow changes in monolayer integrity, the innate immune response and HIV-1 transmission across this barrier. Lastly we will investigate the susceptibility of endocervical T cells in women using DMPA and the LNG-IUD to HIV-1 and test the hypothesis that epithelial mediators increase T cell susceptibility to HIV-1 under low levels of MPA but not high levels of LNG, NOMAC or UL. Understanding the mechanisms underlying increased HIV-1 transmission in women using DMPA and the differential effects of alternative progestins and delivery methods on transmission events will allow informed recommendation of the safest contraceptive methods for use in at-risk women.