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

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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.