Sexual Modulation of HIV-Revelant Vaginal Immunity

描述（由申请人提供）：性传播是妇女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已确定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。由于最近的努力，以提高粘膜防御性传播感染的局部杀微生物剂已经失败，更好地了解FRT免疫是必要的。尽管知道如何FRT生理学变化的阴茎阴道性交（PVI），有一点了解PVI如何影响HIV相关的FRT免疫。拟议的实验测试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感染率的影响，这些实验还详细说明了PVI如何平行改变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。该研究包括三个具体目标：（1）确定PVI对阴道粘膜先天性和适应性免疫的蛋白质介质和全身性性激素浓度的影响;（2）确定PVI对阴道液影响淋巴细胞和巨噬细胞对体外HIV感染易感性的能力的影响;（3）研究PVI对阴道液中抗菌肽（AMP）浓度的影响。将从100名处于长期异性恋关系的绝经前成年女性中获得受试者内数据。女性将参与PVI作为实验条件，并在自己家中控制PVI的重要元素（运动、拥抱、自我刺激和安静时间）的四种活动，在每次活动之前、之后15分钟和之后的早晨（由于与阴道杀微生物剂应用相关而选择的时间）自行收集FRT粘膜和唾液样本并完成自我报告测量。这种重复测量范式将检查与四种社会性质的控制活动相比，肺静脉隔离是否特异性调节FRT免疫。FRT标本将用于定量蛋白质和脂质介质，反映粘膜免疫防御的状态;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相关免疫功能的基础生物学提供新的线索，以进一步了解HIV性传播的环境，NIH已将其确定为了解女性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HIV的新方法产生重大影响。例如，确定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。

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.