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Fine Mechanisms of Adaptive NK Cell Formation Against HIV and SIV

适应性 NK 细胞形成对抗 HIV 和 SIV 的精细机制

基本信息

批准号：
10661657
负责人：
Stephanie Jost
金额：
$ 81.09万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-20 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661657
关键词：
Address Antibodies Antibody-Dependent Enhancement Antigens Autologous B-Lymphocytes Binding Cell Line Cell physiology Cells Clonal Expansion Cytomegalovirus Cytotoxic T-Lymphocytes Data Development Disparate Effector Cell Epigenetic Process Epitopes Exhibits Exposure to Future Gene Expression Profile Genetic Transcription HIV HIV Antigens HIV Infections HIV vaccine Helper-Inducer T-Lymphocyte Hour Human Immune In Vitro Infection Infectious Agent Influenza Innate Immune System Investigation KLRD1 gene Kinetics Laboratories Ligands Mediating Memory Metabolic Molecular Molecular Profiling Mus Natural Killer Cells Outcome Pathway interactions Peptides Persons Play Primates Reporting Role SIV Sampling Specificity T-Lymphocyte Therapeutic Intervention Vaccination Vaccine Design Viral Viral Physiology Virus Virus Diseases Virus Replication design immune function in vivo interest mouse model nonhuman primate prevent programs protective effect receptor response sensitizing antigen single-cell RNA sequencing

项目摘要

The majority of current strategies aiming to prevent, control or eradicate HIV rely on harnessing effector functions of cytotoxic T cells, helper T cells, B cells and antibodies to attack HIV and HIV-infected cells. However, natural killer (NK) cells might represent the ideal subset of antiviral effector cells to promptly and potently respond to HIV exposure. Classically, NK cells are viewed as nonspecific effector cells of the innate immune system that play critical roles in defense against viral infections, including HIV. Besides their ability to rapidly eliminate virus- infected cells without the need for prior antigen sensitization, several independent studies from the past 12 years have demonstrated that subsets of murine, non-human primate (NHP) and human NK cells are capable of adaptive immune functions, including antigen-specificity and recall responses. Our laboratories provided the first clear evidence of antigen-specific NK cell memory in a primate species, elicited by HIV/SIV infection and vaccination. Preliminary data presented in this application now show that antigen-specific NK cell memory with potent antiviral functions develops upon exposure to HIV in humans and provide the first mechanistic evidence for antigen-specific NK cell memory, strongly supporting a role for HLA-E and its activating ligand NKG2C in antigen-specific NK cell responses. Collectively, these findings suggest that antiviral functions of adaptive NK cells have tremendous potential to be exploited for vaccine design, curative or other therapeutic interventions against HIV. However, the most significant obstacles to harnessing adaptive NK cell functions is the opacity surrounding the mechanisms of their formation and their potential to mediate protection in primate species. In this study, we propose to address the overarching hypothesis that adaptive NK cell responses develop kinetically to inhibit SIV/HIV replication and use disparate mechanisms of MHC recognition and alternative epigenetic and metabolic programs through two focused yet independent Aims: (i) Define in vitro and in vivo mechanisms of MHC-E-restricted NK cell antigen specificity against HIV and SIV infections; and (ii) Delineate NK cell-specific molecular programs influencing adaptive NK cell formation against HIV and SIV. Taken together, these investigations will provide critical information on the development of antigen- specific memory NK cells against SIV/HIV and determine the capacity of this NK cell subset to control viral replication. If successful, these studies will identify clear pathways that could be exploited to further enhance adaptive NK cell antiviral activity in future HIV vaccine and/or cure strategies.

目前大多数旨在预防、控制或根除艾滋病毒的策略都依赖于利用效应器功能细胞毒性 T 细胞、辅助 T 细胞、B 细胞和抗体来攻击 HIV 和 HIV 感染细胞。然而，自然杀伤（NK）细胞可能代表抗病毒效应细胞的理想子集，能够迅速有效地应对艾滋病毒暴露。传统上，NK 细胞被视为先天免疫系统的非特异性效应细胞，在防御包括艾滋病毒在内的病毒感染方面发挥着关键作用。除了它们能够快速消灭病毒之外- 过去 12 年的多项独立研究表明，无需事先进行抗原致敏即可感染细胞已经证明鼠科动物、非人类灵长类动物 (NHP) 和人类 NK 细胞的子集能够适应性免疫功能，包括抗原特异性和回忆反应。我们的实验室提供了第一个灵长类动物中存在由 HIV/SIV 感染引起的抗原特异性 NK 细胞记忆的明确证据疫苗接种。本申请中提供的初步数据现在表明，抗原特异性 NK 细胞记忆与人类接触艾滋病毒后会产生有效的抗病毒功能，并提供了第一个机制证据对于抗原特异性 NK 细胞记忆，强烈支持 HLA-E 及其激活配体 NKG2C 在抗原特异性 NK 细胞反应。总的来说，这些发现表明适应性 NK 的抗病毒功能细胞具有用于疫苗设计、治疗或其他治疗干预的巨大潜力对抗艾滋病毒。然而，利用适应性 NK 细胞功能的最大障碍是不透明性围绕它们的形成机制及其介导灵长类物种保护的潜力。在在这项研究中，我们提出解决适应性 NK 细胞反应发展的总体假设动力学上抑制 SIV/HIV 复制并使用不同的 MHC 识别机制和通过两个有重点但独立的目标实现替代表观遗传和代谢计划：(i) 定义体外以及针对 HIV 和 SIV 感染的 MHC-E 限制性 NK 细胞抗原特异性的体内机制； (ii) 描绘影响适应性 NK 细胞形成的 NK 细胞特异性分子程序艾滋病毒和SIV。总而言之，这些研究将提供有关抗原发展的关键信息。针对 SIV/HIV 的特定记忆 NK 细胞，并确定该 NK 细胞亚群控制病毒的能力复制。如果成功，这些研究将确定可用于进一步增强的明确途径未来 HIV 疫苗和/或治疗策略中的适应性 NK 细胞抗病毒活性。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NK cell education: Physiological and pathological influences.

DOI：
10.3389/fimmu.2023.1087155
发表时间：
2023
期刊：
FRONTIERS IN IMMUNOLOGY
影响因子：
7.3
作者：
Rascle, Philippe;Woolley, Griffin;Jost, Stephanie;Manickam, Cordelia;Reeves, R. Keith
通讯作者：
Reeves, R. Keith

Protocol for identification and computational analysis of human natural killer cells using flow cytometry and R.