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: 10534402
• 负责人: Alberto Bosque
• 金额: $ 20.19万
• 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/10534402
• 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; Enhancers; Epigenetic Process; FCGR3B gene; FDA approved; Future; Generations; Goals; HIV; HIV Infections; HIV vaccine; Histone Acetylation; Human; IFNG gene; In Vitro; Individual; Infection; Innate Immune System; Interferon Type II; Interleukin-12; Interleukin-15; Interleukin-18; Interleukin-2; Intervention; Lead; Light; Macaca; Malignant Neoplasms; Mediating; Memory; Modification; Mycobacterium bovis; Natural Killer Cells; Nuclear; Pathway interactions; Peptides; Pharmaceutical Preparations; 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; 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.

项目摘要 天然杀手（NK）细胞是先天免疫系统的一部分，并且在控制艾滋病毒中起着重要作用 感染。已显示NK细胞可以控制非洲绿色的B细胞中的SIV复制 在疫苗接种研究中，猴子在猕猴中获取SHIV的次数下降。此外，研究 在Croi2015和AIDS2018上提出了控制HIV感染的NK细胞的重要性 人类。这些研究表明，来自Visconti的后处理后控制器中的NK响应很强 学习。所有这些先前的研究都强调了利用NK细胞发展受保护的HIV的重要性 疫苗或治疗方法。最近，NK细胞已被证明具有“自适应”或“记忆样”特性。这些 属性在重新刺激后的定量和质量上增加了效应子响应；增强 响应低水平IL-2或IL-15的增殖；体内生存增强；并增强细胞溶解 对不同的恶性肿瘤的反应。在HIV的背景下，现有的类似内存的NK细胞已经 显示在原发性感染期间控制病毒血症。为此，了解信号通路和 促进记忆状NK细胞产生的机制可能导致理论的发展 在疫苗的背景下，增强由记忆样NK细胞介导的HIV控制的策略 开发和治疗干预措施。我们的初步数据支持了以下假设，即记忆样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AIM 1中，我们将定义 信号通路，促进记忆样NK细胞的产生。具体来说，我们将调查 细胞因子，抗体和类似受体的受体激动剂的作用诱导记忆样的NK细胞。中的一个 记忆样NK细胞的标志是IFN-γ基因座的表观遗传重塑，其特征是减少 DNA甲基化并在重新刺激后增强了IFN-γ。因此，我们将研究DNA甲基化 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）调节产生 记忆状的NK细胞。在AIM 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的感染。我们将扩大研究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。这些研究的最终目标 建议将是阐明信号通路，从而增强了类似记忆的产生 NK细胞。如果成功，我们将提供临床前数据以制定干预措施以增强内存样NK 效应子在HIV疫苗接种和/或治疗策略的背景下起作用。