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（HCV））的应答中起着至关重要的作用。与其他淋巴细胞不同，NK细胞缺乏特异性抗原受体，但在靶细胞表面上连接几种经典和非经典主要组织相容性复合体（MHC）后，在来自抑制性和活化性受体库的复合信号整合后消除靶细胞。HCV感染的更好结果与特定NK细胞杀伤免疫球蛋白样受体（KIR）基因及其各自的HLA I类配体的组合表达之间的显著流行病学关联进一步强调了NK细胞在控制HCV感染中的潜在重要性。有趣的是，最近的数据已经表明，HLA等位基因结合的肽中的突变可以改变靶细胞的KIR识别，支持NK细胞功能的一定程度的肽特异性。此外，我们的初步数据结合人口宿主基因组学与病毒测序现在表明，KIR相关的突变可以在HIV中识别，这表明NK细胞能够对病毒施加选择性压力。我们假设NK细胞可以驱动HCV进化，并且NK驱动的突变损害病毒复制能力并有助于免疫控制。因此，本提案的总体目标是研究NK细胞的抗病毒活性及其对HCV演变的影响。将讨论以下具体目标：（1）鉴定与特定KIR/HLA复合物基因型表达相关的HCV序列突变;（2）确定KIR/HLA相关HCV序列突变对NK细胞识别的影响;（3）确定KIR/HLA相关HCV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.