How antigen exposure shapes the subsequent NK cell response to HIV

该提案的目标是确定抗原暴露如何塑造随后的自然杀伤细胞 对艾滋病毒的反应。我们建议在天然和抗原致敏的人NK细胞中鉴定NK功能亚群 使用单细胞测序和多参数流式细胞术。我们建议核实 使用我们建立的体外研究， 和体内功能测定。NK细胞是一种天生的淋巴细胞，其杀伤能力名副其实 感染或肿瘤细胞。然而，NK细胞效应子功能的靶向尚未被发现。 一直是疫苗开发的重要焦点，主要集中在T和B细胞对应物上 在适应性免疫系统中。本申请PI的最新研究结果表明，NK细胞值得 更多关注我们最近发表了令人兴奋的新数据，人类NK细胞记住了先前的抗原- 在人源化小鼠中遇到并介导对HIV-包膜的增强回忆反应。在这里，我们介绍 未发表的新数据表明，HIV-Env引发的记忆NK细胞在实验性病毒感染后抑制HIV病毒滴度。 挑战.这些发现为利用NK记忆功能进行疫苗设计提供了机会。 然而，高NK细胞受体库多样性与HIV感染风险增加相关， 和NK细胞受体库在整个生命过程中多样化，可能是对抗原暴露的反应。 这些数据对疫苗设计提出了挑战，因为保护性NK记忆应答和潜在的免疫应答都是免疫应答。 危险的NK库多样化是抗原暴露的结果。确定具体 HIV应答性、宿主保护性NK细胞的功能亚群及其宿主保护机制， 因此是非常需要的。他们的发现将为改进疫苗设计打开大门， NK记忆的掺入，而不是有害的受体库多样性，作为宿主保护性结果。 我们的数据将使疫苗的预筛选，以诱导保护性NK功能亚群， 临床模型，并允许在人类中改进疫苗效力评估。因此，我们的研究 为开发利用NK细胞的抗病毒活性来保护人类的新型疫苗提供了理论基础 避免艾滋病毒感染，同时避免有害活动。

The goal of this proposal is to determine how antigen exposure shapes subsequent Natural Killer cell responses to HIV. We propose to identify NK functional subsets in naïve and antigen-primed human NK cells using single-cell sequencing and multi-parametric flow cytometry. We propose to verify the relevance of such functional subsets to NK cell-mediated host protection from HIV disease using our established in vitro and in vivo functional assays. NK cells are innate lymphocytes that live up to their name by their ability to kill infected or tumor cells within minutes of exposure. However, the targeting of NK cell effector functions has not been a significant focus in vaccine development, which has mainly focused on their T and B cell counterparts in the adaptive immune system. Recent findings from the PI of this application indicate that NK cells deserve more attention. We recently published exciting new data that human NK cells remember prior antigen- encounters and mediate enhanced recall responses to HIV-Envelope in humanized mice. Here, we present unpublished new data that HIV-Env-primed memory NK cells suppress HIV viral titers upon experimental viral challenge. These findings have opened the opportunity to harness NK memory functions for vaccine design. However, high NK cell receptor repertoire diversity is associated with an increased risk of HIV acquisition, and NK cell receptor repertoires diversify throughout life, presumably in response to antigen exposure. These data present a challenge for vaccine design, as both protective NK memory responses and potentially risky NK repertoire diversifications are consequences of antigen exposure. The identification of specific functional subsets of HIV-responsive, host-protective NK cells and their mechanisms of host protection is therefore critically needed. Their discovery will open the door for revised vaccine designs that endure the incorporation of NK memory, rather than harmful receptor repertoire diversity, as a host protective outcome. Our data will enable the pre-screening of vaccines for the induction of protective NK functional subsets in pre- clinical models and allow for improved vaccine efficacy evaluations in humans. Thereby, our studies will provide the rationale to develop novel vaccines that exploit the antiviral activity of NK cells to protect humans from HIV infection while avoiding harmful activity.