Sexual Modulation of HIV-Revelant Vaginal Immunity

描述(申请人提供)：性传播是女性感染艾滋病毒的主要原因。世界卫生组织和国家卫生研究院都确认迫切需要了解异性恋艾滋病毒传播和女性生殖道的相关生理学，以支持艾滋病毒预防工作。因为最近使用局部杀微生物剂来增强对性传播感染的粘膜防御的努力失败了，所以有必要更好地了解FRT免疫。尽管人们知道阴茎-阴道性交(PVI)后FRT的生理变化，但对PVI如何影响HIV相关的FRT免疫却知之甚少。建议的实验测试PVI对与HIV感染相关的FRT免疫介质的影响。考虑到性激素对HIV感染率的公认影响，这些实验还详细说明了PVI如何同时改变FRT免疫介质和性类固醇。跨学科研究团队由生物医学、性健康和艾滋病毒免疫科学家和医生组成。拟议的研究包括三个具体目标：(1)确定PVI对阴道黏膜天然免疫和获得性免疫的蛋白介质以及全身性激素浓度的影响；(2)确定PVI对阴道液能力的影响，以影响体外培养的淋巴细胞和巨噬细胞对HIV感染的易感性；(3)表征PVI对阴道液中抗菌肽(AMP)浓度的影响。受试者内的数据将来自100名有长期异性关系的绝经前成年女性。女性将参与PVI作为实验条件，并在自己的家中控制PVI的重要元素(锻炼、拥抱、自我刺激和安静时间)的四项活动，自我收集FRT粘膜和唾液样本，并在实验前、15分钟后完成自我报告措施，以及根据与阴道杀菌剂应用的相关性而选择的每项活动后的第二天早上。这种重复测量的范例将检查与四种具有社会性质的控制活动相比，首次免疫反应免疫是否受到PVI的特定调节。FRT样本将用于量化反映粘膜免疫防御状态的蛋白质和脂肪介质；唾液样本将用于测定性类固醇。这项拟议的研究结果将为了解阴道粘膜艾滋病毒相关免疫功能的基本生物学提供新的线索，以进一步了解艾滋病毒的性传播环境，美国国立卫生研究院认为这对了解女性的艾滋病毒感染率至关重要。确定PVI对免疫防御的影响可能会对开发预防或治疗艾滋病毒的新方法产生重大影响。例如，识别受性活动失调的阴道免疫方面，可以为更有效的杀微生物剂的合理设计提供信息。 公共卫生相关性(由申请者提供)：性传播是妇女感染艾滋病毒的主要途径。阴道粘膜中的免疫介质是抵御艾滋病毒的第一道防线，了解性行为如何改变基本的阴道免疫过程，可能会加强努力，制定成功的艾滋病毒预防措施，并遏制性传播艾滋病毒日益增长的发病率。

DESCRIPTION (provided by applicant): Sexual transmission is the major cause of HIV infection in women. Both the World Health Organization and the National Institutes of Health have identified an urgent need for understanding heterosexual HIV transmission and the relevant physiology of the female reproductive tract (FRT) to support HIV prevention efforts. Because recent efforts to enhance mucosal defenses against STIs using topical microbicides have failed, a better understanding of FRT immunity is warranted. Despite knowledge of how FRT physiology changes in response to penile-vaginal intercourse (PVI), there is little understanding of how PVI affects HIV-relevant FRT immunity. Proposed experiments test effects of PVI on FRT immune mediators relevant to HIV infection. Given the acknowledged influence of sex hormones on HIV infection rates, these experiments also detail how PVI changes FRT immune mediators and sex steroids in parallel. The interdisciplinary research team is comprised of biomedical, sexual health, and HIV immune scientists and physicians. The proposed research includes three specific aims: (1) define effects of PVI on protein mediators of innate and adaptive immunity at the vaginal mucosa and systemic sex hormone concentrations; (2) determine effects of PVI on the capacity for vaginal fluids to influence the vulnerability of lymphocytes and macrophages to HIV infection in vitro; (3) characterize the influence of PVI on antimicrobial peptide (AMP) concentrations in vaginal fluid. Within-subject data will be obtained from 100 premenopausal adult women in long-term heterosexual relationships. Women will engage in PVI as the experimental condition, and four activities controlling for important elements of PVI (exercise, cuddling, self-stimulation, and quiet time) in their own homes, self-collecting FRT mucosal and salivary samples and completing self-report measures before, 15 minutes after, and the morning following each activity at times selected because of relevancy to vaginal microbicide applications. This repeated measures paradigm will examine whether FRT immunity is specifically modulated by PVI compared to four control activities of a social nature. FRT specimens will be used to quantify protein and lipid mediators, which reflect the state of mucosal immune defenses; salivary samples will be used to measure sex steroids. Results from the proposed research will shed new light on the basic biology of HIV-relevant immune function at the vaginal mucosa, to further understand the environment for sexual transmission of HIV, which the NIH has identified as critical to understanding HIV infection rates in women. Defining effects of PVI on immune defenses could have a major impact on the development of novel methods for the prevention or treatment of HIV. For example, identifying aspects of vaginal immunity that are dysregulated by sexual activity could inform the rational design of more effective microbicides. PUBLIC HEALTH RELEVANCE (provided by applicant): Sexual transmission is the primary route for HIV infection in women. Immune mediators in the vaginal mucosa are the first line of defense against HIV, and understanding how sexual activity alters basic vaginal immune processes may enhance efforts to develop successful HIV prevention efforts and stem the growing incidence of sexually transmitted HIV.