Sexual Modulation of HIV-Revelant Vaginal Immunity

描述（由申请人提供）：性传播是女性感染艾滋病毒的主要原因。世界卫生组织和美国国立卫生研究院都认为，迫切需要了解异性恋艾滋病毒传播和女性生殖道（FRT）的相关生理学，以支持艾滋病毒预防工作。由于最近使用局部杀微生物剂增强粘膜防御性传播感染的努力失败，因此有必要更好地了解FRT免疫。尽管我们知道阴茎阴道性交（PVI）后FRT的生理变化，但对于PVI如何影响hiv相关的FRT免疫却知之甚少。本实验拟检测PVI对HIV感染相关的FRT免疫介质的影响。鉴于性激素对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。该跨学科研究小组由生物医学、性健康和艾滋病毒免疫科学家和医生组成。拟开展的研究包括三个具体目标：(1)明确PVI对阴道黏膜先天免疫和适应性免疫蛋白介质和全身性激素浓度的影响；(2)在体外确定PVI对阴道分泌液影响淋巴细胞和巨噬细胞对HIV感染易感性的影响；(3)表征PVI对阴道液抗菌肽（AMP）浓度的影响。受试者内数据将从100名长期异性恋的绝经前成年妇女中获得。女性将参与PVI作为实验条件，并在自己家中进行控制PVI重要元素的四项活动（运动，拥抱，自我刺激和安静时间），自我收集FRT粘膜和唾液样本，并在每次活动前，15分钟后和第二天早上完成自我报告测量，这些时间选择是因为与阴道杀微生物剂应用相关。与四种社会性质的对照活动相比，这种重复测量范式将检验是否FRT免疫被PVI特异性调节。FRT标本将用于量化反映粘膜免疫防御状态的蛋白质和脂质介质；唾液样本将用于测量性类固醇。拟议研究的结果将为阴道粘膜HIV相关免疫功能的基本生物学提供新的线索，以进一步了解HIV的性传播环境，这是NIH确定的了解女性HIV感染率的关键。确定PVI对免疫防御的影响可能对开发预防或治疗艾滋病毒的新方法产生重大影响。例如，确定因性活动而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。

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.