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: 8458046
• 负责人: Charles Robert Wira
• 金额: $ 42.88万
• 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/8458046
• 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.

描述(由申请人提供)：迫切需要防止艾滋病毒-1通过性途径传播给妇女。在世界范围内，大约70%的新病例是通过性行为传播的，女性比男性更容易感染。这项提案的总体目标是确定女性生殖道(FRT)在防止病毒传播方面的作用，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。这一建议提出了一种创新的方法来检验这一假设，即在“脆弱窗口”期间，性激素(雌二醇、孕酮)和化学避孕药(口服制剂、皮下埋植剂和阴道环)增强了FRT HIV靶细胞受体的表达和感染/传播，同时降低了干扰素刺激基因(ISG)的表达。定义为月经周期期间，女性最容易因荷尔蒙变化而感染艾滋病毒的时期，即我们假设的女性最有可能感染艾滋病毒的时间。这是一种理解FRT中HIV感染的性质和机制的新方法，它检验了一种假设，即在“窗口”期间，FRT的HIV靶细胞(CD4+T细胞、巨噬细胞、树突状细胞)受体表达和感染/传递增加，而干扰素刺激基因(ISG)表达减少，从而增加HIV感染的风险。该方法有三个原始目标：1)确定月经周期中阴道、宫颈和子宫靶细胞(CD4+T细胞、巨噬细胞和树突状细胞)中HIV受体表达、激活和对HIV感染的敏感性的变化；2)检测性激素/避孕药对FRT中靶细胞的HIV受体表达和HIV敏感性的直接和间接影响；以及3)确定性激素/避孕药在多大程度上抑制细胞内ISG抗HIV活性和增加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，因为它与最有可能感染艾滋病毒的细胞直接相关。了解性激素/避孕药如何通过增加艾滋病毒受体和减少细胞内病毒保护来具体增强艾滋病毒感染，将为制定预防艾滋病毒传播的治疗机制提供知识基础。它还提供了亟需的信息基础，应能加速开发多用途预防技术，以便为妇女提供安全、有效的手段，同时保护自己不受艾滋病毒、其他性传播和生殖道感染和/或意外怀孕的影响。