Pathways modulating memory-like properties in NK cells and their impact on HIV control

项目摘要 自然杀伤(NK)细胞是先天免疫系统的一部分，在控制艾滋病毒方面发挥着重要作用 感染。研究表明，NK细胞可控制非洲绿猪B细胞滤泡中SIV的复制 在一项疫苗接种研究中，SIV病毒在猕猴体内的获得率下降。此外，研究 在CROI2015和AIDS2018上发表强调NK细胞控制艾滋病毒感染的重要性 人类。这些研究表明，Visconi的后处理控制员的NK反应更强 学习。所有这些以前的研究都强调了利用NK细胞来开发保护性艾滋病毒的重要性 疫苗或解药。最近，NK细胞被证明具有“适应性”或“记忆样”的特性。这些 特性包括在重新刺激时数量和质量上增加的效应器反应；增强的 对低水平IL-2或IL-15反应的增殖；提高体内存活率；增强细胞溶解能力 对不同的恶性肿瘤作出反应。在艾滋病毒的背景下，先前存在的记忆样自然杀伤细胞 在初次感染期间显示能控制病毒血症。为此，了解信号通路和 促进记忆样NK细胞生成的机制可能导致治疗的发展 疫苗背景下加强记忆样NK细胞介导的HIV控制的策略 发展和治疗干预措施。我们的初步数据支持记忆样NK细胞的假说 与传统的自然杀伤细胞相比，具有更强的控制艾滋病毒感染的能力。在目标1中，我们将定义 促进记忆样NK细胞生成的信号通路。具体来说，我们将调查 细胞因子、抗体和Toll样受体激动剂诱导记忆样NK细胞的作用。其中一个 记忆样NK细胞的特征是干扰素-γ基因位点的表观遗传重塑，其特征是 DNA甲基化和再刺激后增强的干扰素-γ。因此，我们将调查DNA甲基化是如何 以及其他表观遗传标记，如组蛋白乙酰化和组蛋白甲基化，调节基因的生成 记忆样的NK细胞。在目标2中，我们将进一步研究记忆样NK细胞控制HIV的能力 使用体外和体内两种感染模型。我们将扩大我们的研究范围，包括不同的病毒株和 评估自然细胞毒性和抗体依赖的细胞毒性。这些研究的最终目标是 建议阐明导致增强类记忆生成的信号通路 NK细胞。如果成功，我们将提供临床前数据，以开发增强记忆类NK的干预措施 效应器在艾滋病毒疫苗接种和/或治疗战略的背景下发挥作用。

Project Summary Natural Killer (NK) cells are part of the innate immune system and play an important role in controlling HIV infection. NK cells have been shown to control of SIV replication in the B cell follicles of African Green Monkeys and in the decrease in acquisition of SHIV in macaques in a vaccination study. Furthermore, studies presented at CROI2015 and AIDS2018 highlight the importance of NK cells controlling HIV infection in humans. These studies showed stronger NK responses in post-treatment controllers from the VISCONTI study. All these previous studies highlight the importance of harnessing NK cells to develop a protective HIV vaccine or a cure. Recently NK cells have been shown to have ‘adaptive’ or ‘memory-like’ properties. These properties include a quantitatively and qualitatively increased effector response upon restimulation; enhanced proliferation in response to low levels of IL-2 or IL-15; enhanced survival in vivo; and enhanced cytolytic response against different malignancies. In the context of HIV, pre-existing memory-like NK cells have been shown to control viremia during primary infection. To that end, understanding the signaling pathways and mechanisms promoting the generation of memory-like NK cells could lead to the development of therapeutic strategies to enhance HIV control mediated by memory-like NK cells both in the context of vaccine development and cure interventions. Our preliminary data supports the hypothesis that memory-like NK cells have an enhanced ability to control HIV infection relative to conventional NK cells. In Aim 1, we will define the signaling pathways that promote the generation of memory-like NK cells. Specifically, we will investigate the role of cytokines, antibodies and Toll-like receptor agonists inducing memory-like NK cells. One of the hallmarks of memory-like NK cells is the epigenetic remodeling of the IFN-γ locus characterized by reduced DNA methylation and enhanced IFN-γ upon restimulation. As such, we will investigate how DNA methylation as well as other epigenetic marks such as histone acetylation and histone methylation regulate the generation of memory-like NK cells. In Aim 2, we will further investigate the ability of memory-like NK cells to control HIV infection using both in vitro and in vivo models. We will expand our studies to include different viral strains and evaluate both natural cytotoxicity and antibody-dependent cellular toxicity. The ultimate goal of these research proposal will be to elucidate signaling pathways that lead to the enhancement of the generation of memory-like NK cells. If successful, we will provide preclinical data to develop interventions to enhance memory-like NK effector functions in the context of HIV vaccination and/or cure strategies.