Hepatitis C virus escape mechanisms from innate immunity

丙型肝炎病毒逃避先天免疫的机制

• 批准号: 8234942
• 负责人: Ranjit Ray
• 金额: $ 38.4万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234942
• 关键词: Acute; Antibody Formation; Antigen-Antibody Complex; Antiviral Therapy; Binding; Carrier State; Cell Culture Techniques; Chronic Hepatitis C; Cirrhosis; Complement; Complement Activation; Complementary DNA; Development; Flavivirus; Future; Genes; Genetic Variation; Genotype; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Hypergammaglobulinemia; Immune Complex Diseases; Immune response; Immune system; In Vitro; Infection; Integration Host Factors; Interferon Signaling Modulation Pathway; Interferons; Investigation; Lead; Liver diseases; Measures; Mediating; Modality; Molecular; Natural Immunity; Pathway interactions; Patients; Primary carcinoma of the liver cells; Proteins; Regulation; Replicon; Ribavirin; Sampling; Serum; Staging; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; Variant; Viral; Viral Antibodies; Viral Proteins; Virus; Virus Diseases; Virus Replication; base; biodefense; genetic variant; improved; insight; neutralizing antibody; response; success; virus genetics

Hepatitis C virus (HCV) infects over 170 million people world-wide, causing a spectrum of liver disease ranging from an asymptomatic carrier state to end-stage liver disease. HCV efficiently escapes host immune responses and establishes persistence in >80% of acute cases; however the mechanism is poorly understood. Antiviral therapy with interferon (IFN)-a and ribavirin clears HCV infection in about half of those patients treated, but there is a large variation in IFN-a based treatment efficacy depending on the viral genotype. High viral genetic variation is associated with success of therapy. Persistent HCV infection is associated with hypergammaglobulinemia, high levels of antiviral antibody, circulating immune complexes, and immune complex disease. Infection of immortalized human hepatocytes (IHH) with cell culture grown HCV induces IFN expression, although virus replication is not inhibited. Modest HCV neutralizing antibody response is generated in humans from natural infection, and neutralization can be augmented in vitro by serum complement. Based on these observations, we hypothesize that HCV proteins interact with cellular proteins to promote escape from innate immunity. We will undertake an in-depth investigation of the molecular interactions of HCV or specific HCV proteins and components of the innate immune response. Aim 1 will identify host factors involved in HCV mediated modulation of IFN signaling pathway. Aim 2 will measure the effects of HCV genetic variation on the evasion of IFN-a responses. Aim 3 will investigate the molecular mechanisms for HCV induced complement regulation. Studies will be performed using HCV cDNA from patient samples, replicon, and cell culture grown HCV. Together, these studies will improve our understanding of how viral infections interfere with innate immune responses to promote viral persistence, and will provide future avenues for therapeutic modalities.

丙型肝炎病毒（HCV）感染全球超过1.7亿人，引起一系列肝脏疾病 从无症状的携带者状态到终末期肝病。HCV有效地逃避宿主免疫 反应和建立持久性在>80%的急性病例;然而，机制是差 明白干扰素（IFN）-α和利巴韦林的抗病毒治疗清除了约一半的HCV感染， 患者治疗，但有一个很大的变化，在IFN-α为基础的治疗效果取决于病毒 基因型高病毒遗传变异与治疗成功相关。持续性HCV感染 与高丙种球蛋白血症、高水平抗病毒抗体、循环免疫复合物 和免疫复合物疾病。用生长的细胞培养物感染永生化人肝细胞（IHH） HCV诱导IFN表达，尽管病毒复制不受抑制。中度HCV中和抗体 在人类中，自然感染会产生中和反应，通过以下方法可以在体外增强中和反应： 血清补体基于这些观察，我们假设HCV蛋白与细胞相互作用， 蛋白质，以促进逃避先天免疫。我们将深入调查 HCV或特异性HCV蛋白与先天免疫应答组分的分子相互作用。 目的1：研究HCV介导的干扰素信号通路的宿主因子.目标2将 测量HCV遗传变异对逃避IFN-α应答的影响。目标3将调查 HCV诱导的补体调节的分子机制。将使用HCV进行研究 来自患者样品、复制子和细胞培养物生长的HCV的cDNA。总之，这些研究将改善我们的 了解病毒感染如何干扰先天免疫反应以促进病毒持续存在， 并将为治疗方式提供未来的途径。