Natural killer cells and control of SIV infection

描述（由申请人提供）： 先天免疫应答，包括自然杀伤（NK）细胞应答，是在适应性免疫应答发展之前针对病毒感染的主要防御，并且可以在决定病毒感染的结果中发挥关键作用。越来越多的证据表明，NK反应可以在控制HIV复制方面发挥重要作用。然而，NK细胞在控制HIV/SIV复制中的作用的许多关键问题仍然没有答案，包括粘膜NK应答对病毒遏制的潜在贡献。虽然NK细胞已被确定在胃肠道和泌尿生殖道粘膜，这些细胞已相对较差的特点，很少有人知道他们在正常宿主中的作用。实践和伦理方面的考虑可能会显着限制的努力，以阐明粘膜NK细胞在HIV感染的受试者和检查这些反应在非人灵长类动物的作用的作用，可能会提供最好的机会来解决这些关键问题。我们实验室最近的数据表明，以前未被识别的NK细胞群体在恒河猴的胃肠道和泌尿生殖系统组织，并开发了一套新的技术来表征NK细胞在外周血和粘膜组织。有了这些新的检测方法，并利用约翰逊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NK细胞在SIV感染的猕猴中的作用。具体目标包括：1.研究粘膜NK细胞在阴道攻击后调节SIV感染过程中的作用; 2.研究NK细胞识别SIV感染的CD 4+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。虽然大量的研究表明，自然杀伤细胞帮助人体抵御艾滋病毒感染，但几乎没有人知道粘膜部位的自然杀伤细胞，粘膜部位是人体内传播艾滋病毒和发展艾滋病的最重要组织之一。该提案的目标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，特别强调肠道和女性生殖道中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.