Hepatitis C virus escape mechanisms from innate immunity

丙型肝炎病毒逃避先天免疫的机制

基本信息

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
项目类别：
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

项目摘要

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，导致一系列肝脏疾病从无症状携带者状态到终末期肝病。 HCV 有效逃避宿主免疫在 >80% 的急性病例中做出反应并建立持久性；但机制较差明白了。使用干扰素 (IFN)-a 和利巴韦林进行抗病毒治疗可清除约一半患者的 HCV 感染接受治疗的患者，但基于 IFN-a 的治疗效果存在很大差异，具体取决于病毒基因型。高病毒遗传变异与治疗的成功相关。持续性 HCV 感染是与高丙种球蛋白血症、高水平的抗病毒抗体、循环免疫复合物相关，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，但病毒复制并未受到抑制。适度的 HCV 中和抗体人类因自然感染而产生反应，并且可以通过以下方法在体外增强中和作用：血清补体。基于这些观察，我们假设 HCV 蛋白与细胞相互作用促进逃避先天免疫的蛋白质。我们将深入调查此事 HCV 或特定 HCV 蛋白与先天免疫反应成分的分子相互作用。目标 1 将确定参与 HCV 介导的 IFN 信号通路调节的宿主因子。目标2将测量 HCV 遗传变异对逃避 IFN-a 反应的影响。目标 3 将调查 HCV 诱导补体调节的分子机制。研究将使用 HCV 进行来自患者样本、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，并将为未来的治疗方式提供途径。