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源于艾滋病毒为逃避宿主免疫反应而开发的许多策略。最近，初步鉴定出HIV分离株能够通过辅助HIV蛋白VPU下调人类白细胞抗原-C，导致T细胞失去识别能力。因此，VPU介导的对HLA-C的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。在此背景下，申请人最近表明，表达抑制性KIR2DL受体的NK细胞能够检测到HIV介导的感染细胞表面HLA-C表达的变化。这些高度多态的受体以不同的亲和力识别人类白细胞抗原-C，并主导NK细胞的反应。鉴于人类白细胞抗原-C和KIR2DL受体的广泛多态性，目前尚不清楚KIR2DL/HLA-C同种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介导的人类白细胞抗原-C下调的背景下。基于这些发现，我们假设KIR2DL/HLA-C的相互作用是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。本研究旨在研究在HIV介导的HLA-C下调的背景下，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相互作用对VPU相关病毒在体内和体外进化的影响。使用自体体外感染系统将评估KIR2DL+NK细胞的抗HIV活性。此外，VPU内由NK细胞驱动的病毒进化将通过下一代测序在初级分离株和体外鉴定。总之，这项建议的结果将为NK细胞介导的HIV感染细胞识别的潜在机制以及HIV通过调节HLA-C表达来逃避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.