Fine Mechanisms of Adaptive NK Cell Formation Against HIV and SIV

目前大多数旨在预防、控制或根除艾滋病毒的战略依赖于利用效应器功能 利用细胞毒性T细胞、辅助T细胞、B细胞和抗体攻击HIV和HIV感染细胞。然而，自然 杀伤(NK)细胞可能是抗病毒效应细胞的理想亚群，可以迅速和有效地对其进行反应 暴露于艾滋病病毒。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关键作用。除了快速清除病毒的能力外- 过去12年的几项独立研究表明，感染的细胞不需要事先进行抗原致敏 已经证明小鼠、非人灵长类(NHP)和人类NK细胞亚群能够 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 由HIV/SIV感染和感染引起的灵长类物种中抗原特异性NK细胞记忆的明确证据 接种疫苗。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 在人类接触艾滋病毒的情况下，产生了强大的抗病毒功能，并提供了第一个机制证据 对于抗原特异的NK细胞记忆，强烈支持人类白细胞抗原-E及其激活配体NKG2C在 抗原特异性NK细胞反应。总而言之，这些发现表明适应性NK的抗病毒功能 细胞具有巨大的潜力，可用于疫苗设计、治疗或其他治疗干预 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 围绕它们的形成机制和它们在灵长类物种中调解保护的潜力。在……里面 在这项研究中，我们建议解决适应性NK细胞反应发生的主要假设 动力学地抑制SIV/HIV复制并使用不同的MHC识别和 通过两个有重点但独立的目标的替代表观遗传和代谢计划：(I)在体外确定 MHC-E限制性NK细胞抗原抗HIV和SIV感染的体内机制； 和(Ii)描绘影响适应性NK细胞形成的NK细胞特异性分子程序 HIV和SIV。综上所述，这些研究将提供有关抗原发展的关键信息- 针对SIV/HIV的特异性记忆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，这些研究将确定可以利用的明确途径，以进一步增强 适应性NK细胞在未来HIV疫苗和/或治疗策略中的抗病毒活性。

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.