1998 Fiscal Year Final Research Report Summary
A study on the interferon-resistancy of hepatits C virus
| Project/Area Number |
08457164
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
SATO Chifumi Tokyo Medical and Dental University, Faculty of Medicine, Professor, 医学部, 教授 (60154069)
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| Co-Investigator(Kenkyū-buntansha) |
KUROSAKI Masayuki Tokyo Medical and Dental University, Faculty of Medicine, Assistant, 医学部, 助手 (10280976)
ENOMOTO Nobuyuki Tokyo Medical and Dental University, Faculty of Medicine, Assistant, 医学部, 助手 (20251530)
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| Project Period (FY) |
1996 – 1998
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| Keywords | Hepatitis C virus / Interferon / Chronic hepatitis |
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| Research Abstract |
Previously, we showed that mutations in the NS5A region are closely assiciated with interferon efficacy in hepatitis C virus (HCV) genotype lb infection. In the present study, we studied the relation between interferon efficacy and NSSA mutations in genotype 2 infection. The rate of complete responses was 60% and 30% in genotype 2a and 2b infection, respectively. In both genotypes, there was a positive correlation between the number of mutations in the NS5A region and the response rate to interferon.
The 5'untranslated region (5'UTR) of HCV genome is highly conserved, and serves as an internal ribosomal entry site that initiates the cap-independent translation of HCV polyprotein. Mutations in the 5'UTR has been shown to cause changes in the efficiency of protein translation in vitro. However, the significance of genetic variations of the 5'UTR is not fully known in clinical settings. Therefore, we studied the relation between interferon efficacy and mutatinas in the 5'UTR.Sequence varia
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blilty of the 5'UTR had no influence on inteiferon efficacy or serum HCV-RNA concentrations in clinical settings. These results indicate that diverse clinical pictures among patients with a given genotype of HCV could not be explained by the sequence variability seen in the 5'UTR that is thought to have a key role in both HCV-RNA replication and translation. So far, the NS5A region is considered to be the only site that is associated with interferon efficacy.
To study the mechanism of the difference in interferon sensitivity of the NS5A region, we investigated the transcriptional activation function of the NS5A region and the effect of amino acid mutations in the NS5A region. The NS5A region had a transcriptional activity and it was enhanced by amino acid mutations, which are also related to decreased viral load and increased interferon sensitivity. We then studies the effect of NS5A on the interferon signal transduction system. The NS5A protein of HCV inhibited cellula responses to IFN.This inhibitory effect was more prominent in the wild type NS5A than the mutant type. These observations indicate that the repression of IFN signal transduction pathway by the NS5A protein may be one of the mechanisms through which HCV confers resistance to TEN. Less
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