Natural killer cells and control of SIV infection

描述(由申请人提供)： 先天免疫反应，包括自然杀伤(NK)细胞反应，是在形成获得性免疫反应之前抵抗病毒感染的主要防御措施，在决定病毒感染的结局中发挥着关键作用。越来越多的证据表明，NK反应在控制HIV复制方面可以发挥重要作用。然而，许多关于NK细胞在控制HIV/SIV复制中的作用的关键问题仍然没有得到回答，包括粘膜NK反应对病毒遏制的潜在贡献。虽然NK细胞在胃肠道和泌尿生殖道粘膜中都已被发现，但这些细胞的特征相对较差，对它们在正常宿主中的作用也知之甚少。实际和伦理上的考虑可能会大大限制阐明粘膜NK细胞在HIV感染者中的作用的努力，而研究这些反应在非人类灵长类动物中的作用可能会提供解决这些关键问题的最佳机会。我们实验室的最新数据表明，猕猴胃肠道和泌尿生殖道组织中存在以前未被识别的NK细胞群，并开发了一套新的技术来表征外周血和粘膜组织中的NK细胞。有了这些新的检测方法，并利用约翰逊实验室和哈斯实验室的互补专业知识，我们提出了一套全面的实验来分析自然杀伤细胞在感染SIV的猕猴中的作用。其具体目的包括：1.研究粘膜NK细胞在调节SIV感染过程中的作用；2.研究NK细胞识别SIV感染的CD4+细胞的机制；3.对SIV感染动物NK细胞中KIR表达和功能的扰动进行纵向研究。包括自然杀伤细胞在内的先天免疫反应是抵御艾滋病毒等病毒感染的第一道防线，通常在早期遏制和塑造随后的免疫反应方面发挥关键作用。尽管大量研究表明，自然杀伤细胞有助于人体抵御艾滋病毒感染，但几乎对粘膜部位的自然杀伤细胞知之甚少，粘膜是人体内传播艾滋病毒和发展艾滋病的最重要组织之一。这项建议的目的是研究自然杀伤细胞在感染猴免疫缺陷病毒(SIV)的非人灵长类动物中的作用，特别是对肠道和雌性生殖道中的自然杀伤细胞的研究。

DESCRIPTION (provided by applicant): Innate immune responses, including natural killer (NK) cell responses, are the principal defense against viral infections prior to the development of adaptive immune responses and can play a critical role in determining the outcome of viral infection. Increasing evidence suggests that NK responses can play a significant role in control of HIV replication. However, many critical questions on the role of NK cells in the control of HIV/SIV replication remain unanswered, including the potential contribution of mucosal NK responses to virus containment. Although NK cells have been identified in both gastrointestinal and genitourinary mucosa, these cells have been relatively poorly characterized, and little is known about their role in normal hosts. Practical and ethical considerations are likely to significantly constrain efforts to elucidate the roles of mucosal NK cells in HIV-infected subjects and examination of the role of these responses in nonhuman primates is likely to offer the best opportunity to address these key questions. Recent data from our laboratory have demonstrated previously unrecognized populations of NK cells in gastrointestinal and genitourinary tissues in rhesus macaques and developed a new set of techniques to characterize NK cells in peripheral blood and mucosal tissues. Armed with these new assays and drawing on the complementary expertise of the Johnson and Haase laboratories, we propose a comprehensive set of experiments to analyze the role of NK cells in SIV-infected macaques. Specific aims include: 1. to examine the role of mucosal NK cells in modulating the course of SIV infection following vaginal challenge; 2. to examine the mechanism of recognition of SIV-infected CD4+ cells by NK cells; and 3. to carry out longitudinal studies of perturbations of KIR expression and function in NK cells from SIV-infected animals. Innate immune responses, including natural killer cells, are the first line of defense against viral infections such as HIV, and often play a key role in early containment and in shaping the immune responses that follow. Although a large number of studies suggest that natural killer cells help the body defend itself against HIV infection, almost nothing is known about natural killer cells in mucosal sites, one of the most important tissues in the body for transmission of HIV and development of AIDS. The goal of this proposal is to study the role of natural killer cells in nonhuman primates infected with simian immunodeficiency virus (SIV), with particular emphasis on studies of natural killer cells in the gut and female reproductive tract.