How antigen exposure shapes the subsequent NK cell response to HIV

这项提议的目标是确定抗原暴露如何塑造后续的自然杀伤细胞 对艾滋病毒的反应。我们建议在幼稚和抗原诱导的人NK细胞中鉴定NK功能亚群 采用单细胞测序和多参数流式细胞术。我们建议验证以下内容的相关性 利用我们在体外建立的NK细胞介导的宿主抗HIV疾病的功能亚群 体内功能测定。NK细胞是与生俱来的淋巴细胞，其杀伤力名副其实。 感染或肿瘤细胞在暴露后几分钟内。然而，NK细胞效应器的靶向功能并没有 是疫苗开发中的一个重要焦点，主要集中在T和B细胞对应物上 在适应性免疫系统中。这一应用的PI的最新发现表明，NK细胞应该 更多的关注。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调节对艾滋病毒包膜的增强回忆反应。在这里，我们向大家介绍 未发表的新数据表明，HIV-Env启动的记忆NK细胞在实验病毒上抑制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，NK细胞受体谱系的高度多样性与艾滋病毒感染风险的增加有关， 而NK细胞受体在整个生命过程中都是多样化的，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记忆反应和潜在的 高风险的NK谱系多样化是抗原暴露的后果。特定身份的识别 HIV应答、宿主保护的NK细胞的功能亚群及其宿主保护机制 因此，这是非常需要的。他们的发现将为修改后的疫苗设计打开大门，这些设计将经得起 结合NK记忆，而不是有害的受体多样性，作为宿主保护的结果。 我们的数据将使疫苗的预筛选能够诱导保护性NK功能亚群 临床模型，并允许改进对人体的疫苗效力评估。因此，我们的研究将 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 Here, we present unpublished new data that HIV-Env-primed memory NK cells suppress HIV viral titers upon experimental viral challenge.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.