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NK细胞已被证明可以控制SIV在非洲绿色的B细胞滤泡中的复制 在一项疫苗接种研究中，此外，研究 在CROI 2015和AIDS 2018上提出的研究强调了NK细胞控制HIV感染的重要性， 人类这些研究表明，VISCONTI的治疗后控制者的NK反应更强 study.所有这些先前的研究都强调了利用NK细胞来开发保护性HIV的重要性。 疫苗或治愈方法最近，NK细胞已被证明具有“适应性”或“记忆样”特性。这些 性质包括在再刺激时定量和定性增加的效应器应答;增强的 增殖响应于低水平的IL-2或IL-15;增强的体内存活;和增强的细胞溶解性。 对不同恶性肿瘤的反应。在艾滋病毒的背景下，预先存在的记忆样NK细胞已经被发现， 显示在原发感染期间控制病毒血症。为此，了解信号通路和 促进记忆样NK细胞产生的机制可能会导致治疗性药物的开发。 增强记忆样NK细胞介导的HIV控制的策略， 发展和治疗干预。我们的初步数据支持记忆样NK细胞 相对于常规NK细胞，具有增强的控制HIV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。之一 记忆样NK细胞的标志是IFN-γ基因座的表观遗传重塑，其特征在于减少的免疫应答。 DNA甲基化和再刺激后增强的IFN-γ。因此，我们将研究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， 记忆类NK细胞的细胞。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 感染使用体外和体内模型。我们将扩大我们的研究，包括不同的病毒株， 评价天然细胞毒性和抗体依赖性细胞毒性。这些研究的最终目标 建议将阐明信号通路，导致增强的产生记忆样 NK细胞。如果成功，我们将提供临床前数据，以开发增强记忆样NK的干预措施。 在HIV疫苗接种和/或治愈策略的背景下的效应子功能。

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.