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，大约70%的新病例是通过性交传播的，女性比男性更容易受到感染。本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，使女性在月经周期更容易受到感染。“脆弱性窗口期”是我们假设的妇女最容易感染艾滋病毒的时间，它被定义为月经周期中妇女由于荷尔蒙变化而最容易感染艾滋病毒的时期。这是一种理解FRT中HIV感染的性质和机制的新方法，通过验证在“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，从而增加了HIV感染的风险。该方法有3个最初的目的：1)确定阴道、宫颈和子宫中靶细胞（CD4+ T细胞、巨噬细胞和树突状细胞）的HIV受体表达、激活和对HIV感染的易感性的变化；2)探讨性激素/避孕药具对HIV受体表达和靶细胞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的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地增强HIV感染，将为开发预防HIV传播的治疗机制提供知识基础。它还提供了一个急需的信息基础，应该加速发展多用途预防技术，旨在向妇女提供安全、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。

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.