Modulation of innate immunity,microbiome and HIV transmission by Depo-Provera

Depo-Provera 对先天免疫、微生物组和 HIV 传播的调节

• 批准号: 8885647
• 负责人: Theresa L Chang
• 金额: $ 72.18万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-09 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885647
• 关键词: AIDS prevention; Accounting; Adult; African; Androgens; Animals; Attenuated Vaccines; Biological Process; Biopsy; Blood; CCL2 gene; CCR5 gene; CD4 Positive T Lymphocytes; CXCL10 gene; Cell surface; Cervical; Contraceptive Agents; Contraceptive Usage; Country; Data; Depo Provera; Development; Diagnosis; Ecosystem; Endocervix; Epidemiologic Studies; Family Planning; Feces; Female; Glucocorticoids; Goals; HIV; HIV Infections; Health; Hormonal; Hormones; Host Defense; Human; Immune; Immune response; Immune system; Immunologics; In Vitro; Infection; Injectable; Injection of therapeutic agent; Integrins; Lactobacillus; Lead; Longitudinal Studies; Luteal Phase; Macaca mulatta; Mediating; Mediator of activation protein; Medroxyprogesterone 17-Acetate; Methods; Modeling; Mucosal Immune Responses; Mucous Membrane; Natural Immunity; Peripheral; Play; Police; Predisposition; Prevention strategy; Progesterone; Progestins; Resources; Risk; Role; SIV; Sampling; Sexual Transmission; Sexually Transmitted Diseases; Site; Specimen; Surveys; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Subsets; Taxon; Testing; Time; Vagina; Woman; base; birth control; cervicovaginal; chemokine; design; hormonal contraception; immunoregulation; in vivo; insight; microbiome; proliferative phase Menstrual cycle; pyrosequencing; rRNA Genes; response; simian human immunodeficiency virus; transmission process; vaccine efficacy; vaginal transmission; young woman

DESCRIPTION (provided by applicant): Epidemiologic studies demonstrate that DMPA may increase the risk of HIV acquisition and transmission. Additionally, Depo-Provera has been shown to attenuate the vaccine efficacy to protect rhesus macaques against SIV infection. The impact of hormonal contraceptive use on HIV acquisition and transmission has profound implications for polices on family planning, particularly in countries with high rates of HIV transmission. While progesterone clearly enhances vaginal transmission of SIV/SHIV in rhesus macaques, the effect of progestin-based hormone on HIV acquisition/transmission in women remains unresolved. We hypothesize that injectable DMPA alters immune responses and cervicovaginal and colonic microbiomes, which may lead to increased HIV acquisition and transmission. The aims of this proposal are designed to (1) determine the impact of Depo-Provera on the systemic and mucosal immune systems and on cervicovaginal and colonic microbiomes in a longitudinal study, and (2) to elucidate the immune mechanisms of MPA-mediated modulation of HIV infection/transmission in vitro, ex vivo and in cervical explant models. Blood, cervicovaginal specimens and stool samples will be collected at baseline (both follicular and luteal phases) and after 4, and 8 weeks of DMPA injection. The immunological profiles of CD4+ T cells and their susceptibility to HIV will be characterized. We will determine the temporal impact of DMPA on cervicovaginal and colonic microbiome. Global alteration and changes in specific taxa will be correlated with immunological changes. The results of our studies will provide a better understanding of how DMPA modulates immunologic responses and microbiomes, thereby informing the design of effective HIV prevention strategies.

描述（由申请人提供）：流行病学研究表明 DMPA 可能会增加 HIV 感染和传播的风险。此外，Depo-Provera 已被证明会减弱疫苗保护恒河猴免受 SIV 感染的功效。激素避孕药的使用对艾滋病毒感染和传播的影响对计划生育政策具有深远的影响，特别是在艾滋病毒传播率高的国家。虽然孕激素明显增强了恒河猴中 SIV/SHIV 的阴道传播，但基于孕激素的激素对女性 HIV 获得/传播的影响仍未解决。我们假设注射 DMPA 会改变免疫反应以及宫颈阴道和结肠微生物群，这可能导致 HIV 感染和传播增加。该提案的目的是（1）在纵向研究中确定 Depo-Provera 对全身和粘膜免疫系统以及宫颈阴道和结肠微生物组的影响，以及（2）阐明体外、离体和宫颈外植体模型中 MPA 介导的 HIV 感染/传播调节的免疫机制。将在基线（卵泡期和黄体期）以及 DMPA 注射 4 周和 8 周后收集血液、宫颈阴道标本和粪便样本。 CD4+ T 细胞的免疫学特征及其对 HIV 的易感性将得到表征。我们将确定 DMPA 对宫颈阴道和结肠微生物群的暂时影响。特定分类群的整体改变和变化将与免疫学变化相关。我们的研究结果将有助于更好地了解 DMPA 如何调节免疫反应和微生物组，从而为有效的 HIV 预防策略的设计提供信息。