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

在日本，有200-300万肝炎病毒携带者，约有4.5万名患者死于肝病。在丙型肝炎病毒感染方面，干扰素治疗降低了肝细胞癌的发病率，提高了存活率。然而，通过使用干扰素和利巴韦林联合治疗，大约一半的患者无法获得持续的应答。在乙肝病毒感染方面，拉米夫定等抗病毒药物用于治疗慢性乙型肝炎，但由于出现耐药株，效果有限。通过比较丙型肝炎病毒全序列，我们发现完全应答者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5B区域。在自然过程中，这些应答者比无应答者有更高的突变率。应用复制基因系统复制丙型肝炎病毒，证实利巴韦林对NS5A/5B区有较高的突变率。我们还发现，丙型肝炎病毒IRES上的siRNA可以抑制丙型肝炎病毒的复制。在乙肝病毒感染方面，前C区、C区、C区启动子、S前区突变是肝病发生发展的重要因素。乙肝病毒聚合酶基因突变与拉米夫定耐药的相关性也得到证实。观察到丙型肝炎病毒对NFkB和AP-1表达水平的影响。我们现在正在研究这些变化与治疗效果之间的相关性。

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.