Mechanisms of IL28B genetic variation-mediated clearance of hepatitis C virus

IL28B基因变异介导的丙型肝炎病毒清除机制

• 批准号: 8732600
• 负责人: Jianguo Liu
• 金额: $ 18.75万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732600
• 关键词: Antiviral Therapy; Attention; Binding; Cell Line; Chronic Hepatitis C; Complex; DNA Binding; Data; Disease; Family; Genes; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genotype; Goals; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Immune response; Individual; Infection; Interferons; Liver; Liver Cirrhosis; Liver Failure; Malignant neoplasm of liver; Mediating; Messenger RNA; Modeling; Molecular; Nuclear Protein; Outcome; Patients; Poly I-C; Primary carcinoma of the liver cells; Production; Regulation; Single Nucleotide Polymorphism; Stimulus; System; TNF gene; Tissues; Viral; Virus; Virus Diseases; base; cancer genetics; design; effective therapy; global health; improved; loss of function; member; novel; prevent; promoter; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection is a global health problem with 130-170 million individuals infected worldwide and 3.2 million people infected in the USA. The majority of those infected develop chronic HCV infections, which are a leading cause of liver failure and hepatocellular carcinoma in the US. IFN-¿-based treatment is currently the most effective therapy for HCV infection. Unfortunally, ~50% of HCV patients do not achieve sustained virological response (SVR; ie., viral clearance) during treatment. So, understanding the mechanisms by which IL28B genetic variation modulates clearance of HCV will help us better understand how the IFN lambda system controls viral infection. IL28B (IFN-lambda3) is a member of the recently discovered type III interferon (IFN) family and single nucleotide polymorphisms (SNPs) in the IL28B promoter have been recently shown to strongly associate with spontaneous and treatment-induced clearance of HCV. Among those SNPs, polymorphism rs12979860 C/T is the strongest predictor of SVR to IFN-¿-based treatment in patients with HCV infection. During HCV infection, patients with SNP-C produce more IL28B and have much higher rates of viral clearance compared with patients harboring SNP-T. However, how genetic variations in IL28B gene contribute to different expression of IL28B and HCV clearance is unknown. We found that the expression of IL28B mRNA was significantly reduced in liver tissues of HCV patients and in hepatocytes harboring SNP-T compared with those carrying SNP-C. This differential expression of IL28B was also reflected at the promoter level. Most importantly, we found that a unique nuclear protein DNA binding complex strongly binds to SNP-T but not SNP-C in hepatocytes. Our preliminary data suggest that hepatocytes with SNP-T genotype fail to express high amounts of IL28B due to binding of an unknown transcription factor to IL28B promoter, contributing to the persistence of HCV infection. Since the underlying molecular mechanisms are largely unknown, we propose to determine the differential expression of IL28B in primary human hepatocytes and in liver tissues of HCV patients harboring different SNPs, and identify the unknown transcription factor responsible for the reduced expression of IL28B in hepatocytes carrying SNP-T. Our goals are to elucidate the molecular mechanisms by which IL28B is differentially regulated by genetic variation during HCV infection. This will help us understand how the IFN lambda system controls viral infections, which in turn may help improve antiviral therapies.

描述（由申请人提供）：丙型肝炎病毒（HCV）感染是一个全球性健康问题，全球有 130-1.7 亿人感染，美国有 320 万人感染。其中大多数感染者发展为慢性 HCV 感染。 IFN-¿ 是导致美国肝衰竭和肝细胞癌的原因。不幸的是，基于病毒的治疗是目前治疗 HCV 感染的最有效疗法，约 50% 的 HCV 患者在治疗期间无法实现持续病毒学应答（SVR；即病毒清除）。 HCV 的清除将帮助我们更好地了解 IFN lambda 系统如何控制病毒感染。 IL28B (IFN-lambda3) 是最近发现的 III 型干扰素 (IFN) 家族和单核苷酸的成员。 IL28B 启动子中的多态性 (SNP) 最近已被证明与 HCV 的自发清除和治疗诱导的清除密切相关，在这些 SNP 中，多态性 rs12979860 C/T 是 IFN-¿ 的 SVR 的最强预测因子。在HCV感染期间，与携带SNP-T的患者相比，SNP-C患者产生更多的IL28B并且病毒清除率更高。然而，IL28B基因的遗传变异如何导致IL28B的不同表达。 IL28B 和 HCV 清除率未知。我们发现，与携带 SNP-C 的肝细胞相比，HCV 患者的肝组织和携带 SNP-T 的肝细胞中 IL28B mRNA 的表达显着降低。最重要的是，我们发现独特的核蛋白 DNA 结合复合物与肝细胞中的 SNP-T 强烈结合，但不与 SNP-C 结合。我们的初步数据表明，具有 SNP-T 基因型的肝细胞无法表达。由于未知转录因子与 IL28B 启动子结合而产生大量 IL28B，从而导致 HCV 感染的持续存在。由于潜在的分子机制很大程度上未知，我们建议确定原代人类中 IL28B 的差异表达。我们的目标是阐明 IL28B 在携带 SNP-T 的肝细胞中受到遗传变异差异调节的分子机制。 HCV 感染。这将帮助我们了解 IFN lambda 系统如何控制病毒感染，从而有助于改进抗病毒治疗。