Impact of KIR/HLA-C interactions on the anti-HIV activity of NK cells

KIR/HLA-C 相互作用对 NK 细胞抗 HIV 活性的影响

• 批准号: 410760607
• 负责人: Dr. Christian Körner
• 金额: --
• 依托单位: Leibniz-Institut für Virologie (LIV)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/410760607?language=en
• 关键词: Impact; KIR; HLA; interactions; anti

Infection with the human immune deficiency virus (HIV) remains an eventually fatal disease in the absence of antiretroviral therapy. The difficulties to control the infection partially arise from numerous strategies HIV developed to evade host immune responses. Recently primary HIV isolates were identified that are able to downmodulate HLA-C through the accessory HIV protein Vpu leading to loss of recognition by T cells. Vpu-mediated modulation of HLA-C therefore represents a novel immune evasion mechanism and challenges previously established models. In this context, the applicant recently showed that NK cells expressing inhibitory KIR2DL receptors were able to sense HIV-mediated alterations of HLA-C surface expression on infected cells. These highly polymorphic receptors recognize HLA-C with differential affinities and dominate NK-cell responses. Given the extended polymorphism of HLA-C and KIR2DL receptors it is yet unknown to what extent KIR2DL/HLA-C allotype combinations determine the ability of NK cells to efficiently recognize HIV-infected cells, in particular in the setting of HIV-mediated downmodulation of HLA-C. Based on these findings, we hypothesize that KIR2DL/HLA-C interactions represent a major determinant for the magnitude of NK-cell-mediated immune pressure and potentially impact HIV disease progression. This proposal aims to investigate the impact of KIR2DL/HLA-C interactions on the anti-HIV activity of NK cells in the setting of HIV-mediated HLA-C downmodulation. Furthermore, we seek to determine the effects of KIR2DL/HLA-C interactions on Vpu-associated viral evolution in vivo and in vitro. Using an autologous in vitro infection system the anti-HIV activity of KIR2DL+ NK cells will be assessed. Additionally, NK-cell-driven viral evolution within Vpu will be identified in primary isolates and in vitro through next generation sequencing. Altogether, the results obtained from this proposal will provide critical information on the mechanisms underlying NK-cell-mediated recognition of HIV-infected cells and the ability of HIV to evade NK-cell-mediated immune pressure by modulating HLA-C expression.

在没有抗逆转录病毒疗法的情况下，人类免疫缺陷病毒（艾滋病毒）感染仍然是一种最终致命的疾病。控制感染的困难部分来自于艾滋病毒为逃避宿主免疫反应而开发的许多策略。最近，鉴定了能够通过辅助HIV蛋白Vpu下调HLA-C的原代HIV分离株，导致T细胞识别的丧失。因此，Vpu介导的HLA-C调节代表了一种新的免疫逃避机制，并挑战了先前建立的模型。在这种情况下，申请人最近表明，表达抑制性KIR 2DL受体的NK细胞能够感测感染细胞上HIV介导的HLA-C表面表达的改变。这些高度多态性的受体以不同的亲和力识别HLA-C，并主导NK细胞应答。考虑到HLA-C和KIR 2DL受体的扩展多态性，KIR 2DL/HLA-C同种异型组合在多大程度上决定NK细胞有效识别HIV感染细胞的能力，特别是在HIV介导的HLA-C下调的情况下，还不清楚。基于这些发现，我们假设KIR 2DL/HLA-C相互作用是NK细胞介导的免疫压力大小的主要决定因素，并可能影响HIV疾病的进展。该提案旨在研究在HIV介导的HLA-C下调的情况下，KIR 2DL/HLA-C相互作用对NK细胞抗HIV活性的影响。此外，我们试图确定KIR 2DL/HLA-C相互作用在体内和体外对Vpu相关病毒进化的影响。将使用自体体外感染系统评估KIR 2DL + NK细胞的抗HIV活性。此外，将通过下一代测序在原代分离株和体外鉴定Vpu内NK细胞驱动的病毒进化。总而言之，该提案获得的结果将提供有关NK细胞介导的HIV感染细胞识别机制以及HIV通过调节HLA-C表达逃避NK细胞介导的免疫压力的能力的关键信息。