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）在全球范围内感染了1.7亿多人，引起了多种肝病 从无症状的载体状态到末期肝病。 HCV有效逃脱宿主免疫 在> 80％的急性病例中，反应并建立了持久性；但是机制很差 理解。干扰素（IFN）-A和利巴韦林的抗病毒疗法清除了大约一半的HCV感染 接受治疗的患者，但基于IFN-A的治疗功效有很大的变化 基因型。高病毒遗传变异与治疗成功有关。持续的HCV感染是 与高γ-球素血症，高水平的抗病毒抗体有关，循环免疫复合物， 和免疫复杂疾病。永生的人肝细胞（IHH）感染细胞培养 HCV诱导IFN表达，尽管不抑制病毒复制。适度的HCV中和抗体 人类是由于自然感染而产生的，可以在体外增强中和 血清补体。基于这些观察结果，我们假设HCV蛋白与细胞相互作用 蛋白质促进逃脱先天免疫。我们将对 HCV或特定HCV蛋白的分子相互作用以及先天免疫反应的成分。 AIM 1将确定与HCV介导的IFN信号通路调制有关的宿主因素。 AIM 2意志 测量HCV遗传变异对IFN-A反应逃避的影响。 AIM 3将调查 HCV诱导补体调控的分子机制。研究将使用HCV进行 来自患者样品，复制子和细胞培养的HCV的cDNA。这些研究将共同​​改善我们的 了解病毒感染如何干扰先天免疫​​反应以促进病毒持久性， 并将为治疗方式提供未来的途径。