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Analysis of Viral and host factors influencing the pathophysiology and effect of therapy of pesisitent hepatitis virus infection

影响顽固性肝炎病毒感染病理生理及治疗效果的病毒及宿主因素分析

基本信息

批准号：
16590576
负责人：
YOKOSUKA Osamu
金额：
$ 2.24万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

In Japan, there are 2-3 million hepatitis virus carriers and approximately 45,000 patients die due to liver diseases. Regarding HCV infection, reduced incidence of t hepatocellular carcinoma and improved survival rate are observed by interferon (IFN) treatment. However, by using IFN and ribavirin combination therapy, about half of the patients cannot get a sustained response. Regarding HBV infection, antiviral agent such as lamivudine is used for chronic hepatitis B, but the effect is limited due to emergence of resistant strain. By comparing the whole HCV sequence, we have shown that complete- and partial-responders have higher mutation rate than non-responders, especially in non-structual protein (NS) 5A and 5B regions. Higher mutation rates are observed during the natural course in these responders than in non-responders. By applying the replicon system that is a model for HCV replication, higher rate of mutation in NS5A/5B regions by ribavirin was confirmed. We have also shown that replication of HCV can be suppressed by siRNA on IRES of HCV. Regarding HBV infection, precore, core, core promoter, pre-S mutations are revealed to be important factors for the advance in liver disease. The correlation between the mutation in HBV polymerase and lamivudine resistance was also demonstrated. The expression level of NFkB and AP-1 was observed to be influenced by HCV. We are now examining the correlation between these changes and treatment effect.

在日本，有2-3百万肝炎病毒携带者，大约45，000名患者死于肝病。关于HCV感染，通过干扰素（IFN）治疗观察到肝细胞癌的发病率降低和生存率提高。然而，使用干扰素和利巴韦林联合治疗，约一半的患者不能获得持续的反应。关于HBV感染，抗病毒药物如拉米夫定用于慢性B型肝炎，但由于出现耐药株，效果有限。通过比较整个HCV序列，我们已经表明，完全和部分应答者比无应答者有更高的突变率，特别是在非结构蛋白（NS）5A和5 B区域。在自然病程中观察到这些应答者的突变率高于无应答者。通过应用作为HCV复制模型的复制子系统，证实了利巴韦林在NS 5A/5 B区域中的较高突变率。我们还表明，HCV的IRES上的SiRNA可以抑制HCV的复制。关于HBV感染，前C、核心、核心启动子、前S突变被揭示为肝脏疾病进展的重要因素。HBV多聚酶突变与拉米夫定耐药的关系也得到了证实。观察到NFkB和AP-1的表达水平受HCV影响。我们现正研究这些变化与治疗效果之间的关系。