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: 9089848
• 负责人: ALISON J. QUAYLE
• 金额: $ 39.18万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089848
• 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; Health; 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 Load result; Virus Replication; Woman; contraceptive efficacy; high risk; improved; monolayer; progesterone receptor B; receptor binding; reproductive tract; response; reversible contraceptive; 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）：尽管醋酸甲羟孕酮（depo-MPA、DMPA）具有可用性、可负担性和功效，但人们仍担心它会增加女性对 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。类固醇的避孕作用高度依赖于受体结合和局部浓度，猕猴研究说明了宫颈内膜在 SIV 传播中的重要性。尽管如此，还没有关于使用这些药物的女性中任何避孕孕激素的局部宫颈内浓度的数据。预计全身输送的 DMPA 会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 HIV 在宫颈内膜中的传播。作为 DMPA 的替代品，左炔诺孕酮 (LNG)、醋酸诺美孕烯 (NOMAC) 和 PR 调节剂乌利司他 (UL) 对 GR 的亲和力较差，可能会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 可以保护子宫颈内膜的物理和先天上皮屏障，并减少该部位的 HIV-1 传播。我们将使用 DMPA、一种释放 LNG 的宫内节育器和含孕激素的阴道环来测量女性子宫颈内的孕激素水平，并评估孕激素类型和给药方法对宫颈粘液对 HIV-1 的物理和免疫屏障的影响。接下来，我们将把极化的、激素反应性宫颈内膜上皮细胞暴露于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 HIV-1 穿过这一屏障的传播的变化。最后，我们将研究使用 DMPA 和 LNG-IUD 的女性宫颈内 T 细胞对 HIV-1 的敏感性，并检验以下假设：上皮介质在低水平 MPA 但在高水平 LNG、NOMAC 或 UL 下不会增加 T 细胞对 HIV-1 的易感性。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给药方法对传播事件的不同影响，将有助于为高危妇女提供最安全的避孕方法的明智建议。