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）感染是一个全球性的健康问题，全球有1.3 - 1.7亿人感染，美国有320万人感染。大多数感染者发展为慢性HCV感染，这是美国肝衰竭和肝细胞癌的主要原因。基于IFN-γ的治疗是目前治疗HCV感染最有效的方法。不幸的是，约50%的HCV患者没有达到持续的病毒学应答（SVR;即，病毒清除）。因此，了解IL 28 B基因变异调节HCV清除的机制将有助于我们更好地了解IFN λ系统如何控制病毒感染。IL 28 B（IFN-B3）是最近发现的III型干扰素（IFN）家族的成员，并且IL 28 B启动子中的单核苷酸多态性（SNP）最近已显示与HCV的自发和治疗诱导的清除强烈相关。在这些SNPs中，多态性rs 12979860 C/T是HCV感染患者对基于IFN-γ治疗的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IL 28 B，并且具有更高的病毒清除率。然而，IL 28 B基因的遗传变异如何导致IL 28 B和HCV清除的不同表达尚不清楚。我们发现，与携带SNP-C的肝细胞相比，HCV患者肝组织和携带SNP-T的肝细胞中IL 28 B mRNA的表达显著降低。IL 28 B的这种差异表达也反映在启动子水平。最重要的是，我们发现一种独特的核蛋白DNA结合复合物与肝细胞中的SNP-T而不是SNP-C强烈结合。我们的初步数据表明，SNP-T基因型的肝细胞不能表达大量的IL-28 B，由于一个未知的转录因子结合到IL-28 B启动子，导致HCV感染的持续性。由于潜在的分子机制在很大程度上是未知的，我们建议确定IL 28 B的差异表达在原代人肝细胞和HCV患者的肝组织中携带不同的SNPs，并确定未知的转录因子负责携带SNP-T的肝细胞中IL 28 B的表达减少。我们的目标是阐明HCV感染过程中IL 28 B受遗传变异差异调节的分子机制。这将帮助我们了解IFN λ系统如何控制病毒感染，这反过来可能有助于改善抗病毒疗法。