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

调节 NK 细胞记忆样特性的途径及其对 HIV 控制的影响

• 批准号: 10673150
• 负责人: Alberto Bosque
• 金额: $ 24.23万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10673150
• 关键词: Activated Natural Killer Cell; Address; African Green Monkey; Aftercare; Agonist; Animal Model; Antibodies; Antigens; Area; Attenuated; Autologous; B-Cell Activation; B-Lymphocytes; BCG Live; Bacillus; Bovine Tuberculosis; Cells; Characteristics; DNA Methylation; Data; Development; Drug Modulation; Enhancers; Epigenetic Process; FCGR3B gene; FDA approved; Future; Generations; Goals; HIV; HIV Infections; HIV vaccine; Histone Acetylation; Human; IFNG gene; IL18 gene; In Vitro; Individual; Infection; Innate Immune System; Interferon Type II; Interleukin-12; Interleukin-15; Interleukin-2; Intervention; Light; Macaca; Malignant Neoplasms; Mediating; Memory; Modification; Mycobacterium bovis; Natural Killer Cells; Nuclear; Pathway interactions; Peptides; Play; Primary Infection; Proliferating; Property; Research; Research Proposals; Role; SIV; Signal Pathway; Signal Transduction; TNF gene; Testing; Toll-like receptors; Toxic effect; Transcriptional Activation; Transducers; Vaccination; Viral; Viremia; Virus; Virus Replication; antibody-dependent cell cytotoxicity; comparative efficacy; cytokine; cytotoxicity; histone methylation; humanized mouse; in vivo; in vivo Model; mouse model; pre-clinical; response; simian human immunodeficiency virus; therapeutic development; transcription factor; vaccination against tuberculosis; vaccine development; vaccine trial

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.

项目概要 自然杀伤 (NK) 细胞是先天免疫系统的一部分，在控制 HIV 方面发挥着重要作用 感染。 NK 细胞已被证明可以控制非洲绿 B 细胞滤泡中的 SIV 复制 猴子以及在疫苗接种研究中猕猴感染 SHIV 的减少。此外，研究 在 CROI2015 和 AIDS2018 上发表的论文强调了 NK 细胞控制 HIV 感染的重要性 人类。这些研究表明 VISCONTI 的治疗后控制器有更强的 NK 反应 学习。所有这些先前的研究都强调了利用 NK 细胞开发保护性 HIV 的重要性 疫苗或治疗方法。最近，NK 细胞被证明具有“适应性”或“类记忆”特性。这些 特性包括在再刺激时在数量和质量上增加的效应器反应；增强型 低水平 IL-2 或 IL-15 导致的增殖；提高体内存活率；和增强的细胞溶解作用 针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 细胞已被 显示可控制原发感染期间的病毒血症。为此，了解信号通路并 促进记忆样 NK 细胞生成的机制可能会导致治疗药物的开发 在疫苗背景下增强记忆样 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这样的假设：记忆样 NK 细胞 相对于传统的 NK 细胞，其控制 HIV 感染的能力更强。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 样受体激动剂在诱导记忆样 NK 细胞中的作用。中的一个 记忆样 NK 细胞的标志是 IFN-γ 位点的表观遗传重塑，其特征是减少 再刺激后 DNA 甲基化和 IFN-γ 增强。因此，我们将研究 DNA 甲基化如何 以及其他表观遗传标记，例如组蛋白乙酰化和组蛋白甲基化，调节生成 记忆样 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 使用体外和体内模型进行感染。我们将扩大我们的研究范围，以包括不同的病毒株和 评估天然细胞毒性和抗体依赖性细胞毒性。这些研究的最终目的 提案将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来开发增强记忆样 NK 的干预措施 HIV 疫苗接种和/或治疗策略中的效应器功能。