Menstrual Cycle Control of HIV Infection in the Reproductive Tract

描述（由申请人提供）：迫切需要防止HIV-1通过性传播给妇女。在世界范围内，所有新病例中约有70%是通过性交传播的，妇女比男子更有可能被感染。该提案的总体目标是确定女性生殖道（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，使女性在月经周期中更容易感染。该提案提出了一种创新的方法来测试假设，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，皮下植入物和阴道环）增强FRT HIV靶细胞受体表达和感染/传播，同时降低干扰素刺激基因（ISG）的表达。“脆弱窗口期”被定义为月经周期中妇女由于荷尔蒙变化最容易感染艾滋病毒的时期，我们假设妇女最有可能感染艾滋病毒的时间。这是一种新的方法来理解HIV感染的性质和机制的FRT，通过测试的假设，在“窗口”，FRT HIV-靶细胞（CD 4 +T细胞，巨噬细胞，树突状细胞）受体的表达和感染/传输增加，而干扰素刺激基因（ISG）的表达减少，从而增加了HIV感染的风险。这种方法有3个最初的目的，将：1）定义HIV受体表达的变化，激活和靶细胞对HIV感染的易感性（CD 4 + T细胞、巨噬细胞和树突状细胞）; 2）检查性激素/避孕药对FRT中靶细胞的HIV受体表达和HIV易感性的直接和间接影响;和3）确定性激素/避孕药抑制细胞内ISG抗HIV活性和增加FRT中靶细胞的HIV感染的程度。这项研究的独特之处在于它整合了我们对整个人类FRT内分泌系统和免疫系统的理解，因为它直接关系到最有可能被HIV感染的细胞。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，应能加速开发多用途预防技术，为妇女提供安全、有效的保护手段，同时防止艾滋病毒、其他性传播感染和生殖道感染，和（或）意外怀孕。

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.