Impact of NK Cell Immune Pressures on HCV Evolution and Viral Fitness

描述(由申请人提供)：越来越多的证据表明，先天性免疫系统，特别是自然杀伤(NK)细胞，在宿主对病毒感染(包括丙型肝炎病毒)的反应中发挥着至关重要的作用。与其他淋巴细胞不同，NK细胞缺乏特异的抗原受体，但在结合靶细胞表面几种经典和非经典的主要组织相容性复合体(MHC)后，通过整合来自一系列抑制和激活受体的复杂信号来消除靶细胞。丙型肝炎病毒感染的良好预后与特定的NK细胞杀伤细胞免疫球蛋白样受体(KIR)基因及其各自的HLAI类配体的联合表达之间的显著流行病学联系进一步强调了NK细胞在控制丙型肝炎病毒感染中的潜在重要性。有趣的是，最近的数据表明，与HLA等位基因结合的多肽的突变可以改变靶细胞对KIR的识别，支持一定程度的多肽对NK细胞功能的特异性。此外，我们结合群体宿主基因组学和病毒测序的初步数据现在表明，可以在HIV中发现KIR相关突变，这表明NK细胞能够对病毒施加选择性压力。在这项建议中，我们假设NK细胞可以推动丙型肝炎病毒的进化，NK细胞驱动的突变正在削弱病毒复制能力，并有助于免疫控制。因此，这项建议的总体目标是研究NK细胞的抗病毒活性及其对丙型肝炎病毒进化的影响。具体目标如下：(1)鉴定与特定KIR/HLA复合基因型表达相关的丙型肝炎病毒序列突变；(2)确定与KIR/HLA相关的丙型肝炎病毒序列突变对NK细胞识别的影响；(3)确定与KIR/HLA相关的丙型肝炎病毒序列突变对病毒复制的影响。

DESCRIPTION (provided by applicant): Increasing evidence demonstrates a crucial role of the innate immune system, and in particular natural killer (NK) cells, in the host's response against viral infection, including hepatitis C virus (HCV). Unlike other lymphocytes, NK cells lack specific antigen receptors, but eliminate target cells following the integration of complex signals from an arsenal of inhibitory and activating receptors upon ligation of several classical and non-classical major histocompatibility complexes (MHC) on the surface of target cells. The significant epidemiological association between better outcome from HCV infection and the combined expression of particular NK cell killer immunoglobulin-like receptor (KIR) genes together with their respective HLA class I ligand further emphasizes the potential importance of NK cells in the control of HCV infection. Interestingly, recent data has illustrated that mutations in peptides bound by HLA alleles can alter KIR recognition of target cells, supporting some degree of peptide-specificity to NK cell function. Furthermore, our preliminary data combining population host genomics with viral sequencing now suggests that KIR-associated mutations can be identified in HIV, suggesting that NK cells are capable of exerting selective pressures upon viruses. We hypothesize in this proposal that NK cells can drive HCV evolution, and that NK-driven mutations are impairing viral replication capacity and contributing to immune control. Thus, the overall objective of this proposal is to study the antiviral activity of NK cells and their impact on HCV evolution. The following specific aims will be addressed: (1) Identification of HCV sequence mutations associated with the expression of specific KIR/HLA compound genotypes; (2) Determine the impact of KIR/HLA-associated HCV sequence mutations on NK cell recognition; and (3) Determine the impact of KIR/HLA-associated HCV-sequence mutations on viral replication.