Prevention of HIV transmission/acquisition through informed contraceptive choice

通过知情避孕选择预防艾滋病毒传播/获得

• 批准号: 8706037
• 负责人: ALISON J. QUAYLE
• 金额: $ 49.91万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-25 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8706037
• 关键词: AIDS prevention; Acetates; Address; Affinity; Androgen Receptor; Antiviral Agents; Biological Response Modifiers; CD4 Positive T Lymphocytes; Cell model; Cervix Mucus; Clinical; Clinical Research; Cohort Studies; Contraceptive Agents; Contraceptive methods; Contracts; Data; Down-Regulation; Endocervix; Enrollment; Epithelial; Epithelial Cells; Epithelium; Event; Female; Genital system; Glucocorticoid Receptor; HIV; HIV-1; High Risk Woman; Hormone Responsive; Human; Immune; Immune response; In Vitro; Infant; Infection; Injectable; Injection of therapeutic agent; Intrauterine Devices; Investigation; Knowledge; Laboratories; Leukocytes; Levonorgestrel; Macaca; Measures; Mediating; Mediator of activation protein; Medroxyprogesterone 17-Acetate; Methods; Modeling; Mothers; Mucous body substance; Pharmaceutical Preparations; Physiological; Predisposition; Production; Progesterone Receptors; Progestins; Recommendation; Risk; Risk Factors; SIV; Safety; Serum; Sexual Transmission; Site; Steroids; System; T-Lymphocyte; Testing; Vaginal Ring; Viral; Viral Load result; Woman; contraceptive efficacy; high risk; improved; monolayer; progesterone receptor B; public health relevance; receptor binding; reproductive; response; transmission process

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.

描述（由申请人提供）：尽管具有可用性，负担能力和功效，但人们担心DEPO甲状腺乙酸丙酸酯（DEPO-MPA，DMPA）会增加妇女对HIV-1的敏感性。因此，我们寻求对避孕孕激素对HIV-1传播的影响的改进知识。避孕类固醇的作用高度依赖于受体结合和局部浓度，而猕猴研究说明了内部核在SIV传播中的重要性。尽管如此，尚无关于使用这些药物的女性孕妇孕激素的局部宫颈浓度的数据。预计全身传递的DMPA会产生低生殖道的MPA。 MPA对糖皮质激素受体（GR）的强亲和力可能使其能够调节促进内核中HIV传播的免疫和物理上皮屏障功能。作为DMPA的替代品，左甲虫（LNG），Nomegantrel乙酸盐（NOMAC）和PR调节剂Ulipristal（UL）对GR的亲和力较差，并且可能以高局部浓度递送至生殖道。我们假设与低水平的MPA不同，高水平的LNG，NOMAC或UL，可以保护内部核的物理和先天上皮屏障，并减少该站点的HIV-1传播。我们将使用DMPA，富含LNG的宫内节育器和含孕激素的阴道环，评估孕激素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，我们将揭示极化的激素响应性肠上皮细胞到避孕孕激素的生理水平，并遵循单层完整性的变化，跨该障碍的先天免疫反应和HIV-1传播。最后，我们将研究使用DMPA和LNG-IUD对HIV-1的宫颈T细胞在女性中的敏感性，并测试上皮介体在MPA水平较低但LNG，NOMAC，NOMAC或UL水平较高的情况下增加T细胞对HIV-1的敏感性。了解使用DMPA的女性HIV-1传播的基础机制以及替代孕激素的差异效应以及输送方法对传播事件的差异效应将允许对处于危险的妇女使用最安全的避孕方法的明智建议。