IL-28B genotype and HCV treatment clearance

IL-28B 基因型和 HCV 治疗清除率

• 批准号: 8885642
• 负责人: Srikanta Dash
• 金额: $ 37.63万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885642
• 关键词: Address; Adult; Antiviral Agents; Antiviral Response; Applications Grants; Autophagocytosis; Biological; Caring; Cell Culture System; Cell Culture Techniques; Cell Line; Cells; Chronic; Chronic Hepatitis C; Clinical Trials; Combined Modality Therapy; FDA approved; Fractionation; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Health; Hepatitis C; Hepatitis C virus; Hepatocyte; Interferon-alpha; Interferons; Internal Ribosome Entry Site; Investigation; Knowledge; Link; Liver; Liver Cirrhosis; MAP Kinase Gene; Malignant neoplasm of liver; Messenger RNA; MicroRNAs; Nuclear Translocation; Nucleoside Transporter; Outcome; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phosphorylation; Play; Polyribosomes; Primary carcinoma of the liver cells; Printing; Production; Protease Inhibitor; Proto-Oncogene Proteins c-akt; Reporting; Resistance; Ribavirin; Ribosomes; Role; Signal Transduction; Stress; System; Testing; Therapeutic; Toes; Translations; United States; Viral; Virus Diseases; Virus Replication; base; chronic liver disease; genetic association; genome wide association study; improved; interferon alpha receptor; liver transplantation; novel strategies; prevent; receptor; resistance mechanism; response; success; tissue culture; treatment response; type I interferon receptor; uptake; viral resistance

DESCRIPTION (provided by applicant): The sustained antiviral response of chronic HCV infection has been improved recently by the use of the protease inhibitor (telaprevir or boceprevir) along with interferon alpha (IFN-α) and ribavirin. However, results of recent clinical trials indicate that the final outcome of triple combination therapy is strongly dependent on the patient's initial response to IFN-α plus ribavirin and the host genetic variation of IL-28 gene polymorphism. The biological mechanisms underpinning this association remain unknown. The current application explores mechanisms for how the IFN-λ axis is linked to the success of IFN-α/ribavirin treatment using a stable and persistently infected HCV cell culture system. The proposal is based on several exciting and encouraging preliminary studies. We have developed a persistently HCV infected cell culture system that supports high- level viral replication to address the antiviral mechanisms of IFN-α and ribavirin combination treatment. We reported that HCV infection itself induces ER-stress and autophagy response that selectively down regulates the type-I IFN receptor but not the type-II or type-III IFN receptor, impaired Stat1/Stat phopshorylation, nuclear translocation, defective Jak-Stat signaling and impaired antiviral response. We have reported that ribavirin and IFNα each inhibit HCV IRES translation and synergistically inhibit HCV replication. The ribavirin resistance mechanism relates to the impaired ribavirin uptake due to the down-regulated expression nucleoside transporters in HCV cell culture. Our results indicate that IFN-? has a strong antiviral action against HCV and it clears HCV replication to a completion in Jak-Stat defective and persistently infected HCV cell culture system through activation of Stat3, AKT and MAPK pathways suggesting that the type III IFN system plays a very important role in the clearance of HCV infection. In this R01 application, we will focus on understanding the mechanism underlying the association between IL28B polymorphisms and IFN-α/ribavirin antiviral mechanisms of HCV infection in a persistent infectious cell culture system in hepatocyte cell lines with a different genetic background of IL-28B gene. Our hypothesis is that hepatitis C virus infection itself creates defective Jak-Stat signaling by down regulating the expression of IFNAR1 that leads to impaired response to pegylated IFN-α and ribavirin. To test this hypothesis we propose the following three Specific Aims. Aim 1: To test hypothesis that the IFN-λ axis is important for HCV clearance and treatment using a persistently infected HCV cell culture. Aim 2: Study the mechanisms by which IFN-λ overcome IFN-α resistance of persistent HCV infection. Aim 3: To investigate the synergy and resistance mechanism of ribavirin in HCV infection. Since IFN-λ clears HCV replication in Jak-Stat defective IFN-α resistant cells, understanding the signal transduction and anti-viral mechanism of IFN-λ proposed in this grant application should open novel strategies for the treatment of chronic HCV infection.

描述（由申请人提供）：最近通过使用蛋白酶抑制剂（特拉匹韦或波普匹韦）以及干扰素α（IFN-α）和利巴韦林，慢性HCV感染的持续抗病毒反应得到了改善。然而，最近的临床试验结果。表明三联疗法的最终结果强烈依赖于患者对IFN-α加利巴韦林的初始反应以及IL-28基因多态性的宿主遗传变异的生物学机制。目前的应用探索了 IFN-λ 轴如何与使用稳定且持续感染的 HCV 细胞培养系统进行 IFN-α/利巴韦林治疗的成功相关的机制。我们开发了一种持续感染 HCV 的细胞培养系统，该系统支持高水平病毒复制，以解决 IFN-α 和利巴韦林联合治疗的抗病毒机制。我们已经报道，利巴韦林和抗病毒反应会选择性下调 I 型 IFN 受体而不是 II 型或 III 型 IFN 受体的自噬反应、Stat1/Stat 磷酸化受损、核易位、Jak-Stat 信号传导缺陷和抗病毒反应受损。 IFNα各自抑制HCV IRES翻译并协同抑制HCV复制。利巴韦林耐药机制与由于核苷表达下调而导致的利巴韦林摄取受损有关。我们的结果表明，IFN-α 对 HCV 具有很强的抗病毒作用，并且它通过激活 Stat3、AKT 和 MAPK 途径来清除 Jak-Stat 缺陷和持续感染的 HCV 细胞培养系统中的 HCV 复制。 III型干扰素系统在清除HCV感染中发挥着非常重要的作用。在本次R01应用中，我们将重点了解IL28B多态性与HCV感染之间关联的机制。 IFN-α/利巴韦林在具有不同 IL-28B 基因遗传背景的肝细胞系中持续感染细胞培养系统中 HCV 感染的抗病毒机制我们的假设是，丙型肝炎病毒感染本身通过下调而产生有缺陷的 Jak-Stat 信号传导。 IFNAR1 的表达导致对聚乙二醇化 IFN-α 和利巴韦林的反应受损 为了检验这一假设，我们提出以下三个具体目标 1：检验假设。 IFN-λ 轴对于使用持续感染的 HCV 细胞培养物进行 HCV 清除和治疗非常重要。 目标 2：研究 IFN-λ 克服持续性 HCV 感染的 IFN-α 耐药性的机制。 目标 3：研究协同作用和耐药机制。由于 IFN-λ 可以清除 Jak-Stat 缺陷的 IFN-α 耐药细胞中的 HCV 复制，因此了解本次资助中提出的 IFN-λ 的信号转导和抗病毒机制。其应用将为治疗慢性丙型肝炎病毒感染开辟新的策略。