Immunologic changes associated with three progestin-based contraceptives: characterizing immune profiles over one year and identifying factors that may alter HIV risk

与三种孕激素避孕药相关的免疫学变化：描述一年内的免疫特征并确定可能改变艾滋病毒风险的因素

• 批准号: 10201695
• 负责人: Lisa Blake Haddad
• 金额: $ 74.96万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201695
• 关键词: 16S ribosomal RNA sequencing; AIDS/HIV problem; Adherence; Affect; African; Area; Bacterial Vaginosis; Biological Assay; Blood specimen; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Chronic; Clinical; Contraceptive Agents; Contraceptive Usage; Contraceptive methods; Counseling; Cytometry; Data; Decision Making; Disease; Dose; Drug Kinetics; Epidemiology; Escherichia coli; Estrogen Antagonists; Estrogens; Etonogestrel; Exposure to; Female; Female genitalia; Flow Cytometry; Formulation; Genital; Genitalia; Gonadal Steroid Hormones; HIV; HIV Infections; HIV risk; Immune; Immune Targeting; Immune response; Immunologic Factors; Immunologic Markers; Immunologics; Implant; Incidence; Individual; Intrauterine Devices; Lead; Levonorgestrel; Link; Mediating; Medroxyprogesterone 17-Acetate; Menorrhagia; Methods; Mucous Membrane; Nature; Outcome; Outcome Study; Patients; Pharmacology; Polycystic Ovary Syndrome; Predisposition; Prevention; Progestins; Provider; Public Health; Publishing; Recommendation; Reporting; Reproductive Health; Research; Research Design; Research Project Grants; Risk; Risk Factors; Role; Sample Size; Sexually Transmitted Diseases; Testing; Time; Tissues; Translational Research; Vagina; Visit; Woman; aged; base; cohort; comparative; cytokine; endometriosis; epidemiology study; follow-up; global health; hormonal contraception; infection risk; modifiable risk; novel; personalized decision; prospective; recruit; reproductive; reproductive tract; response; unintended pregnancy; vaginal microbiome; vaginal microbiota; volunteer

PROJECT SUMMARY/ABSTRACT This proposal outlines a 5-year translational research project to explore the mechanisms underlying the HIV risk associated with pharmacologic doses of exogenous sex hormones (via hormonal contraceptives). Emerging data suggests that certain hormonal contraceptives may induce mucosal and systemic immune changes that could increase the risk of infection with HIV. While several studies have aimed to characterize immunologic changes in women using hormonal contraceptives, the nature and the magnitude of these immune changes have not been adequately defined due to limitations in study design rigor, and small and statistically underpowered sample sizes. There is limited comprehensive data or comparative data on the effect of different types of contraceptives on innate and adaptive immunologic markers of HIV susceptibility. Without this research, we cannot effectively counsel our patients on contraceptive selection. Characterization of potential individual-level factors, such as the presence of bacterial vaginosis (BV), that may alter a woman's risk profile with contraceptive use, could lead to individualized decision-making about contraceptive choice and would have profound implications for global health especially in HIV-endemic areas. We propose to prospectively recruit cohorts of HIV-uninfected women initiating hormonal contraception to characterize systemic and lower genital track innate and adaptive immunologic changes that occur over the course of 1 year. This study will test the overarching hypothesis that hormonal contraceptives induce systemic and mucosal immune changes capable of altering susceptibilities and/or responses to diseases including HIV infection, and that these effects vary markedly in nature and magnitude by contraceptive type and will be modified by the vaginal microenvironment. The aims are: 1) To determine the immunologic alterations in female genital and systemic immune profile associated with depot medroxyprogesterone acetate (DMPA), Etonogestrel impant (Eng-Implant) and Levonorgestrel IUD (Lng-IUD). We hypothesize that HIV target immune cells within the female genital tract of HIV-uninfected at-risk women will increase following contraceptive initiation. Further, because the anticipated mucosal immune changes with progestin-only contraceptives are, to a large extent, mediated via estrogen suppression, we hypothesize the impact of the Lng-IUD (with minimal to no anti-estrogen effect) and Eng-Implant (with milder anti-estrogen effect) will be significantly less pronounced compared with that of DMPA. 2) To evaluate the vaginal microenvironment as a moderator of genital and systemic immune profile changes and changes in tissue infectivity following exposure to these three commonly used hormonal contraceptives. Based on our earlier findings, we hypothesize that immunologic changes induced with hormonal contraception will be more pronounced in the setting of BV. The outcomes of the proposed study could have significant global clinical implications for safe individualized contraceptive counseling and decision-making for women at risk for HIV/AIDS.

项目概要/摘要 该提案概述了一个为期 5 年的转化研究项目，旨在探索艾滋病毒的潜在机制 与外源性激素药理剂量（通过激素避孕药）相关的风险。 新数据表明，某些激素避孕药可能会诱导粘膜和全身免疫 可能会增加感染艾滋病毒风险的变化。虽然多项研究旨在表征 使用激素避孕药的女性的免疫学变化，这些变化的性质和程度 由于研究设计严格性的限制以及小而多的免疫变化尚未得到充分定义 统计上样本量不足。效果综合数据或对比数据有限 不同类型避孕药对艾滋病毒易感性先天性和适应性免疫标志物的影响。没有 这项研究中，我们无法有效地为患者提供避孕选择方面的咨询。表征 潜在的个人因素，例如细菌性阴道病（BV）的存在，可能会改变女性的 避孕药具使用的风险状况可能会导致有关避孕药具选择的个性化决策 将对全球健康尤其是艾滋病毒流行地区产生深远影响。我们建议 前瞻性招募未感染艾滋病毒且开始激素避孕的女性群体来表征 全身和下生殖器跟踪在 1 的过程中发生的先天性和适应性免疫变化 年。这项研究将检验这一总体假设，即激素避孕药会导致全身性和 粘膜免疫变化能够改变对艾滋病毒等疾病的敏感性和/或反应 感染，并且这些影响在性质和程度上因避孕类型的不同而显着不同，并且将 受阴道微环境的改变。目的是： 1) 确定免疫学改变 与长效醋酸甲羟孕酮 (DMPA) 相关的女性生殖器和全身免疫特征， 依托孕烯植入剂 (Eng-Implant) 和左炔诺孕酮宫内节育器 (Lng-IUD)。我们假设 HIV 的目标是免疫 未感染艾滋病毒的高危女性女性生殖道内的细胞在避孕后会增加 引发。此外，由于纯孕激素避孕药预期的粘膜免疫变化是 在很大程度上，通过雌激素抑制介导，我们假设 Lng-IUD 的影响（最小到 无抗雌激素作用）和 Eng-Implant（具有较温和的抗雌激素作用）将明显不那么明显 与DMPA相比。 2) 评估阴道微环境作为生殖器和性功能的调节因素 暴露于这三种物质后，全身免疫谱的变化和组织感染性的变化通常 使用激素避孕药。根据我们早期的发现，我们假设免疫学变化 在患有 BV 的情况下，激素避孕引起的副作用会更加明显。的结果 拟议的研究可能对安全个体化避孕具有重大的全球临床意义 为面临艾滋病毒/艾滋病风险的妇女提供咨询和决策。