Fine Mechanisms of Adaptive NK Cell Formation Against HIV and SIV

目前旨在预防、控制或根除艾滋病毒的大多数战略都依赖于利用效应器功能 细胞毒性T细胞，辅助性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）细胞可能是理想的抗病毒效应细胞亚群，可以迅速有效地对 艾滋病毒感染。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。除了能快速清除病毒外 感染的细胞，而不需要事先抗原致敏，几个独立的研究，从过去12年 已经证明鼠、非人灵长类动物（NHP）和人NK细胞的亚群能够 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 HIV/SIV感染引起的灵长类动物中抗原特异性NK细胞记忆的明确证据， 预防针本申请中提供的初步数据现在显示，具有抗原特异性NK细胞记忆的NK细胞可以被激活。 在人类暴露于HIV后，产生了强有力的抗病毒功能，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及其活化配体NKG 2C在 抗原特异性NK细胞应答。总的来说，这些发现表明适应性NK细胞的抗病毒功能 细胞在疫苗设计、治疗或其他治疗干预方面具有巨大的潜力 对抗艾滋病病毒。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在灵长类物种中介导保护的潜力。在 这项研究，我们提出解决的总体假设，适应性NK细胞反应发展 在动力学上抑制SIV/HIV复制，并使用不同的MHC识别机制， 通过两个集中但独立的目的替代表观遗传和代谢程序：（i）体外定义 以及MHC-E限制性NK细胞抗原特异性对抗HIV和SIV感染的体内机制; 和（ii）描述影响适应性NK细胞形成的NK细胞特异性分子程序， 艾滋病毒和SIV。总之，这些研究将提供关于抗原开发的关键信息- 针对SIV/HIV的特异性记忆NK细胞，并确定该NK细胞亚群控制病毒感染的能力。 复制的如果成功，这些研究将确定明确的途径，可用于进一步提高 适应性NK细胞抗病毒活性在未来的艾滋病毒疫苗和/或治愈策略。

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.