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

NK 细胞免疫压力对 HCV 进化和病毒适应性的影响

• 批准号: 7554119
• 负责人: TODD M ALLEN
• 金额: $ 22.03万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7554119
• 关键词: Acute Hepatitis C; Address; Alleles; Amino Acids; Antigen Receptors; Antigens; Antiviral Agents; Binding; CD8B1 gene; Cell physiology; Cells; Complex; Consensus; Cytolysis; Data; Development; Disease; Drug Delivery Systems; Effector Cell; Epidemiology; Evolution; Genes; Genomics; Genotype; HIV; HLA-B Antigens; HLA-B57; HLA-C Antigens; Hepatitis C; Hepatitis C virus; Human; Immune; Immune response; Immune system; Individual; Infection; KIR3DS1; Lead; Ligands; Ligation; Link; Liver; Liver Cirrhosis; Liver Failure; Lymphocyte; Major Histocompatibility Complex; Mononuclear; Mutation; Natural Killer Cells; Outcome; Pan Genus; Peptides; Population; Primary carcinoma of the liver cells; Receptor Cell; Receptor Gene; Regulation; Resolution; Role; SIV; Shapes; Signal Transduction; Specificity; Supporting Cell; Surface; T-Lymphocyte; Vaccine Antigen; Vaccines; Viral; Virus; Virus Diseases; Virus Replication; Work; antiretroviral therapy; cost; effective therapy; fitness; improved; killer immunoglobulin-like receptor; member; pathogen; pressure; protective effect; receptor; response; therapeutic vaccine; transmission process

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.

描述（由申请人提供）：越来越多的证据表明，先天免疫系统，尤其是天然杀伤（NK）细胞在宿主对病毒感染的反应中的关键作用，包括丙型肝炎病毒（HCV）。与其他淋巴细胞不同，NK细胞缺乏特定的抗原受体，但在将几种经典和非经典和非经典的主要组织相容性复合物（MHC）连接后，从抑制性的砷和激活受体中整合复杂信号后消除了靶细胞。来自HCV感染的更好预后与特定NK细胞杀手型免疫球蛋白样受体（KIR）基因的综合表达之间的显着流行病学关联与它们各自的HLA I类配体进一步强调了NK细胞在HCV感染控制中的潜在重要性。有趣的是，最近的数据表明，受HLA等位基因结合的肽中的突变可以改变KIR对靶细胞的识别，从而支持某种程度的肽特异性对NK细胞功能。此外，我们的初步数据将种群宿主基因组学与病毒测序结合在一起表明，可以在HIV中鉴定与KIR相关的突变，这表明NK细胞能够对病毒施加选择性压力。我们在这一建议中假设NK细胞可以驱动HCV的演化，而NK驱动的突变会损害病毒复制能力并有助于免疫控制。因此，该提案的总体目的是研究NK细胞的抗病毒活性及其对HCV进化的影响。将解决以下特定目标：（1）鉴定与特定KIR/HLA化合物基因型的表达相关的HCV序列突变； （2）确定KIR/HLA相关的HCV序列突变对NK细胞识别的影响； （3）确定KIR/HLA相关的HCV序列突变对病毒复制的影响。