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

在没有抗逆转录病毒治疗的情况下，感染人类免疫缺陷病毒（艾滋病毒）仍然是一种最终致命的疾病。控制感染的困难部分来自于HIV开发了许多逃避宿主免疫反应的策略。最近发现，原代HIV分离物能够通过辅助HIV蛋白Vpu下调HLA-C，从而导致T细胞失去对其的识别。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KIR2DL受体的NK细胞能够感知hiv介导的感染细胞上HLA-C表面表达的改变。这些高度多态性的受体识别HLA-C具有不同的亲和力，并主导nk细胞反应。鉴于HLA-C和KIR2DL受体的扩展多态性，目前尚不清楚KIR2DL/HLA-C异型组合在多大程度上决定了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。基于这些发现，我们假设KIR2DL/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疾病进展。本研究旨在探讨在hiv介导的HLA-C下调的情况下，KIR2DL/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KIR2DL/HLA-C相互作用在体内和体外对vpu相关病毒进化的影响。使用自体体外感染系统评估KIR2DL+ NK细胞的抗hiv活性。此外，通过下一代测序，将在初代分离株和体外鉴定Vpu内nk细胞驱动的病毒进化。总之，从该提案中获得的结果将为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提供关键信息。

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.