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（由适用提供）：最近通过使用蛋白酶抑制剂（Telaprevir或Boceprevir）以及干扰素α（IFN-α）和利哈维林，通过使用蛋白酶抑制剂（telaprevir或Boceprevir）改善了慢性HCV感染的持续抗病毒反应。但是，最近的临床试验的结果表明，三合一组合疗法的最终结果在很大程度上取决于患者对IFN-α和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。支撑该关联的生物学机制仍然未知。当前的应用探讨了如何使用稳定且持续感染的HCV细胞培养系统与IFN-λ轴如何与IFN-α/利巴韦林处理的成功联系起来的机制。该提案基于一些令人兴奋和令人鼓舞的初步研究。 We have developed a persistently infected cell culture system that supports high-level viral replication 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.我们报告说，利巴韦林和IFNα每个都抑制HCV IRES的翻译，并协同抑制HCV复制。利巴韦林的耐药机制与HCV细胞培养中的核苷核转运蛋白下调有关，与利巴韦林的摄取受损有关。我们的结果表明IFN-？针对HCV具有强烈的抗病毒作用，它通过激活STAT3，AKT和MAPK途径来清除HCV的复制，使JAK-StAT缺陷且持续感染的HCV细胞培养系统的完成，这表明III IIII IFN系统在清除HCV感染中起着非常重要的作用。在此R01应用中，我们将重点放在理解IL28B多态性与HCV感染中IL28B多态性与IFN-α/利巴韦林抗病毒机制之间的关联机制，该机制在肝细胞细胞系中持续感染细胞培养系统中具有不同的IL-28B基因的遗传背景。我们的假设是，丙型肝炎病毒感染本身会通过下调IFNAR1的表达而导致对质量的IFN-α和利巴韦林的反应受损而产生有缺陷的JAK-STAT信号传导。为了检验这一假设，我们提出以下三个特定目标。目的1：检验假设，即IFN-λ轴对使用持续感染的HCV细胞培养物对HCV清除和处理很重要。目标2：研究IFN-λ克服持续性HCV感染的IFN-α抗性的机制。目标3：研究利巴韦林在HCV感染中的协同和抗性机制。由于IFN-λ清除了JAK-STAT缺陷IFN-α耐药细胞中的HCV复制，因此了解本赠款应用中提出的IFN-λ的信号转移和抗病毒机制应开放新的策略，以治疗慢性HCV感染。