Prevention of HIV transmission/acquisition through informed contraceptive choice

描述（由申请人提供）：尽管其可用性，可负担性和疗效，但人们担心醋酸甲羟孕酮（depo-MPA，DMPA）会增加妇女对HIV-1的易感性。因此，我们寻求更好地了解避孕孕激素对HIV-1传播的影响。避孕类固醇的作用高度依赖于受体结合和局部浓度，猕猴研究表明宫颈内膜在SIV传播中的重要性。然而，目前还没有关于使用这些药物的妇女的任何避孕孕激素的局部宫颈内浓度的数据。预计全身递送的DMPA产生低生殖道浓度的MPA。MPA对糖皮质激素受体（GR）的强亲和力可能使其能够调节免疫和物理上皮屏障功能，从而促进宫颈内膜中的HIV传播。作为DMPA的替代品，左炔诺孕酮（LNG）、醋酸诺美孕酮（NOMAC）和PR调节剂ulipristal（UL）对GR的亲和力较差，可以高局部浓度递送至生殖道。我们推测，高水平的LNG，NOMAC或UL，不像低水平的MPA，保护子宫颈内膜的物理和先天上皮屏障，并减少HIV-1在这个网站上的传播。我们将测量使用DMPA、释放LNG的IUD和含孕激素的阴道环的妇女宫颈内膜中的孕酮水平，并评估孕酮类型和递送方法对宫颈粘液对HIV-1的物理和免疫屏障的影响。接下来，我们将使极化的、对子宫颈内膜敏感的上皮细胞暴露于生理水平的避孕孕激素，并跟踪单层完整性、先天免疫应答和HIV-1穿过这一屏障的传播的变化。最后，我们将调查使用DMPA和LNG-IUD的妇女宫颈内T细胞对HIV-1的易感性，并检验上皮介质在低水平MPA下增加T细胞对HIV-1的易感性而不是高水平LNG，NOMAC或UL的假设。了解使用DMPA的妇女中HIV-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，将允许为高危妇女提供最安全的避孕方法的知情建议。

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.