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）感染了全球超过1.7亿人，导致一系列肝脏疾病