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: 8376773
• 负责人: Ranjit Ray
• 金额: $ 16.01万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8376773
• 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(丙型肝炎病毒)感染全球超过1.7亿人，导致一系列肝病 从无症状的携带者状态到终末期肝病。丙型肝炎病毒有效逃避宿主免疫 80%的急性病例有反应并建立持续性；但其机制很差 明白了。干扰素-a和利巴韦林联合抗病毒治疗可清除约一半患者的丙型肝炎病毒感染 患者得到了治疗，但基于干扰素-a的治疗效果因病毒而异。 基因分型。高度的病毒基因变异与治疗的成功有关。持续的丙型肝炎病毒感染 与高丙种球蛋白血症，高水平的抗病毒抗体，循环免疫复合体， 和免疫复合体疾病。永生化人肝细胞(IHH)对培养细胞的感染 虽然病毒复制不受抑制，但丙型肝炎病毒可诱导干扰素表达。温和的丙型肝炎病毒中和抗体 人类对自然感染产生反应，体外中和可通过以下方式增强 血清补体。基于这些观察，我们假设丙型肝炎病毒蛋白与细胞相互作用。 促进逃避先天免疫的蛋白质。我们会深入调查 丙型肝炎病毒或特定的丙型肝炎病毒蛋白和先天免疫反应成分之间的分子相互作用。 目的1确定丙型肝炎病毒介导的干扰素信号通路调控的宿主因素。目标2将 检测丙型肝炎病毒基因变异对逃避干扰素-α反应的影响。目标3将调查 丙型肝炎病毒诱导补体调节的分子机制。将使用丙型肝炎病毒进行研究 从患者样本、复制子和细胞培养中获得丙型肝炎病毒的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久性， 并将为未来的治疗方式提供途径。