Menstrual Cycle Control of HIV Infection in the Reproductive Tract

月经周期控制生殖道艾滋病毒感染

• 批准号: 8317878
• 负责人: Charles Robert Wira
• 金额: $ 46.72万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8317878
• 关键词: Blood; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cervical; Cervix Uteri; Chemicals; Coitus; Combined Oral Contraceptives; Contraceptive Agents; Contraceptive Usage; Dendritic Cells; Depressed mood; Development; Endocrine; Endocrine system; Estradiol; Female; Foundations; Gene Expression; Genes; Goals; Gonadal Steroid Hormones; Growth Factor; HIV; HIV Infections; HIV Receptors; HIV-1; Hormonal Change; Hormones; Immune; Immune system; Implant; Individual; Infection; Interferons; Knowledge; Laboratories; Life; Measures; Mediating; Menstrual cycle; Nature; Oral Contraceptives; Ovulation; Play; Postmenopause; Predisposition; Prevent viral transmission; Prevention; Progesterone; Reproductive Tract Infections; Research; Risk; Role; Sexual Transmission; Staging; Synthetic Progestogens; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Vagina; Vaginal Ring; Viral; Woman; Women' s Role; chemokine; cytokine; design; human female; innovation; knowledge base; macrophage; men; monocyte; novel strategies; pandemic disease; permissiveness; prevent; receptor expression; reproductive; subcutaneous; transmission process; unintended pregnancy; xenoestrogen

DESCRIPTION (provided by applicant): An urgent need exists to prevent the sexual transmission of HIV-1 to women. Worldwide, approximately 70% of all new cases are spread by sexual intercourse, with women more likely to be infected than men. The overall objective of this proposal is to define the role of the female reproductive tract (FRT) in preventing viral transmission and to understand how sex hormones modulate FRT HIV target cells to make women more susceptible to infection during the menstrual cycle. This proposal presents an innovative approach to test the hypothesis that during the "window of vulnerability", sex hormones (estradiol, progesterone) and chemical contraceptives (oral preparations, subcutaneous implants, and vaginal rings) enhance FRT HIV-target cell receptor expression and infection/ transmission while decreasing interferon-stimulated gene (ISG) expression. Defined as the period during the menstrual cycle when women are most susceptible to HIV infection due to hormonal changes, the "window of vulnerability" is the time hypothesized by us when women are most likely to be infected by HIV. This is a novel approach for understanding the nature and mechanisms of HIV infection in the FRT, by testing the hypothesis that during the "window", FRT HIV-target cell (CD4+T cells, macrophages, dendritic cells) receptor expression and infection/ transmission increases while interferon-stimulated gene (ISG) expression decreases, thus increasing the risk of HIV infection. This approach has 3 original Aims that will: 1) Define the changes in HIV receptor expression, activation and susceptibility to HIV infection of target cells (CD4+ T cells, macrophages and dendritic cells) in the vagina, cervix and uterus during the menstrual cycle; 2) Examine the direct and indirect effects of sex hormones/contraceptives on HIV receptor expression and HIV-susceptibility of target cells in the FRT; and 3) Determine to what extent sex hormones/contraceptives suppress intracellular ISG anti-HIV activity and increase HIV infection of target cells in the FRT. This study is unique in tht it integrates our understanding of the endocrine system and the immune system throughout the human FRT as it relates directly to the very cells most likely to be infected by HIV. Understanding how sex hormones/contraceptives specifically enhance HIV infection by increasing HIV receptors and decreasing intracellular viral protection will provide a basis of knowledge for developing therapeutic mechanisms to prevent transmission of HIV. It further provides a much needed foundation of information that should accelerate the development of multipurpose prevention technologies designed to provide women with safe, effective means of protecting themselves simultaneously from HIV, other sexually transmitted and reproductive tract infections, and/or unintended pregnancy. PUBLIC HEALTH RELEVANCE: An urgent need exists to prevent the sexual transmission of HIV-1 to women. Worldwide, approximately 70% of all new cases are spread by sexual intercourse, with women more likely to be infected than men. The object of this research is to develop a clear understanding of how sex hormones and chemical contraceptives (oral preparations, subcutaneous implants, and vaginal rings) enhance HIV infection of HIV-target cells (CD4+T cells, macrophages, dendritic cells) in the FRT during the "window of vulnerability" portion of the menstrual cycle when immune protection is depressed and when HIV infection most likely to occur.

描述（由申请人提供）：迫切需要防止 HIV-1 通过性行为传播给女性。在全球范围内，大约 70% 的新病例是通过性交传播的，女性比男性更容易被感染。该提案的总体目标是明确女性生殖道 (FRT) 在预防病毒传播中的作用，并了解性激素如何调节 FRT HIV 靶细胞，使女性在月经周期更容易受到感染。该提案提出了一种创新方法来检验以下假设：在“脆弱窗口”期间，性激素（雌二醇、黄体酮）和化学避孕药（口服制剂、皮下植入物和阴道环）会增强 FRT HIV 靶细胞受体的表达和感染/传输同时减少干扰素刺激基因（ISG）的表达。 “脆弱窗口”被定义为女性在月经周期中由于荷尔蒙变化而最容易感染艾滋病毒的时期，我们假设女性最有可能感染艾滋病毒的时间。这是一种了解 FRT 中 HIV 感染的性质和机制的新方法，通过测试以下假设：在“窗口”期间，FRT HIV 靶细胞（CD4+T 细胞、巨噬细胞、树突状细胞）受体表达和感染/传播增加，而干扰素刺激基因（ISG）表达减少，从而增加感染艾滋病毒的风险。该方法有 3 个最初目标： 1) 确定月经周期期间阴道、子宫颈和子宫中的靶细胞（CD4+ T 细胞、巨噬细胞和树突细胞）的 HIV 受体表达、激活和对 HIV 感染的易感性的变化； 2) 检查性激素/避孕药对 FRT 中靶细胞 HIV 受体表达和 HIV 易感性的直接和间接影响； 3) 确定性激素/避孕药在多大程度上抑制细胞内 ISG 抗 HIV 活性并增加 FRT 中靶细胞的 HIV 感染。这项研究的独特之处在于它整合了我们对整个人类 FRT 中内分泌系统和免疫系统的理解，因为它与最有可能被 HIV 感染的细胞直接相关。了解性激素/避孕药如何通过增加 HIV 受体和减少细胞内病毒保护来特异性增强 HIV 感染，将为开发预防 HIV 传播的治疗机制提供知识基础。它还提供了急需的信息基础，应加速多用途预防技术的开发，旨在为妇女提供安全、有效的手段，同时保护自己免受艾滋病毒、其他性传播和生殖道感染和/或意外怀孕的影响。 公共卫生相关性：迫切需要防止 HIV-1 通过性行为传播给女性。在全球范围内，大约 70% 的新病例是通过性交传播的，女性比男性更容易被感染。本研究的目的是清楚地了解性激素和化学避孕药（口服制剂、皮下埋植剂和阴道环）如何增强体内 HIV 靶细胞（CD4+T 细胞、巨噬细胞、树突状细胞）的 HIV 感染。 FRT 在月经周期的“脆弱窗口”部分进行，此时免疫保护受到抑制并且最有可能发生艾滋病毒感染。