Innate Immune Protection Against HIV-1 by Reproductive Tract Epithelial Cells

描述(申请人提供)：这项研究的总体目标是了解人类女性生殖道(FRT)上皮细胞在针对HIV-1的先天免疫保护中所起的作用。作为先天免疫防御的哨兵，生殖道上皮细胞是防止性传播感染的第一道防线，对于协调对潜在病毒病原体的快速反应至关重要。我们在这项提案中的目标是检验这一假设，即来自美国白人、非裔美国人和坦桑尼亚妇女的上皮细胞表现出细胞内和分泌的抗病毒活性，保护生殖道免受艾滋病毒-1的感染。本研究项目的具体目的是回答以下问题：1)上皮细胞分泌物在多大程度上保护女性生殖道免受HIV-1的感染？2)细胞内抗病毒因子是否抑制HIV-1的复制？3)候选局部杀菌剂对上皮细胞的天然防御能力有多大影响？4)上皮细胞是否影响底层基质中的T细胞和巨噬细胞感染HIV-1的风险？5)坦桑尼亚妇女的FRT上皮细胞是否表现出针对HIV-1的分泌和/或细胞内保护机制？我们计划使用来自整个女性生殖道和生殖道细胞系的人类原代上皮细胞来研究这些问题，因为这些细胞可以感染HIV-1，能够预防HIV-1感染，并且对性激素有反应。这项建议中描述的研究将进一步加深我们对参与防御HIV-1的粘膜免疫反应的理解，并应导致确定增强保护性反应的方法。这些研究应为开发更有效的杀微生物剂和治疗干预措施提供必要的知识基础。

DESCRIPTION (provided by applicant): The overall objective of this research is to understand the role that human female reproductive tract (FRT) epithelial cells play in innate immune protection against HIV-1. As sentinels of innate immune defense, epithelial cells throughout the reproductive tract are the first line of protection against sexually transmitted infections and are crucial for orchestrating a rapid response to potential viral pathogens. Our goal in this proposal is to test the hypothesis that epithelial cells from White-American, African- American, and Tanzanian women exhibit intracellular and secreted antiviral activity that protects the reproductive tract against HIV-1. The specific aims of the current research project are to answer the following questions: 1) To what extent do epithelial cell secretions protect the female reproductive tract from HIV-1? 2) Do intracellular antiviral factors inhibit HIV-1 replication? 3) To what extent do candidate topical microbicides affect epithelial cell innate defenses? 4) Do epithelial cells influence the risk of HIV-1 infection of T cells and macrophages in the underlying stromal FRT? 5) Do FRT epithelial cells from Tanzanian women exhibit secreted and/or intracellular mechanisms of protection against HIV-1? We plan to investigate these questions using human primary epithelial cells from throughout the female reproductive tract and reproductive tract cell lines, since these cells are infectable by HIV-1, capable of protecting against HIV-1 infection, and responsive to sex hormones. The research described in this proposal will further our understanding of the mucosal immune responses involved in defending against HIV-1 and should lead to the identification of ways to augment protective responses. These studies should provide the basis of knowledge essential for the development of more effective microbicides and therapeutic interventions.