1995 Fiscal Year Final Research Report Summary
Mechanisms of persistent infection and interferon resistance of hepatits C virus
| Project/Area Number |
05454243
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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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, Prefessor, 医学部, 教授 (60154069)
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| Co-Investigator(Kenkyū-buntansha) |
ENOMOTO Nobuyuki Tokyo Medical and Dental University, Faculty of Medicine, Assistant, 医学部, 助手 (20251530)
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| Project Period (FY) |
1993 – 1995
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| Keywords | Hepatitis C virus / Interferon / Chronic hepatitis |
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| Research Abstract |
The hypervariable region of predominant hepatitis C virus (HCV) genomes detected in serum by direct sequencing changes rapidly and serially along the course of acute and chronic HCV infection, suggesting that these changes in the hypervariable region may be one of the mechanisms of recurrence and persistence of HCV infection. These changes are also observed during interferon treatment. Analysis of populations of circulating HCV genomes by the single strand conformation polymorphism (SSCP) method targeted to the hypervariable region has further clarified that they are composed of quasispecies and that predominant HCV quasispecies change during chronic infection and interferon treatment. These changes appear to result from either evolution or selection of the hypervariable region in vivo. Similar changes in the liver are also suggested. There are interferonsensitive and interferon-resistant quasispecies, and this difference in the sensitivity may be determined by the specific sequence of a part of the NS5A region. The whole genome of hepatitis C virus (HCV) genotype 1b with different sensitivity to interferon were studied in same individuals to determine the genetic basis of their resistance. Comparative nucleotide sequence analysis of the whole genome from three pairs of sensitive and resistant HCV isolates identified the cluster of amino acid differences in the NS5 region. Additional sequence data of the NS5A region obtained from interferon resistant HCV and interferon sensitive HCV confirmed the exclusive existence of missense mutations in the NS5A.On the other hand, interferon-resistant HCV from interferon non-responders had the NS5A identical to that of prototype HCV-1b. These results indicated that HCV-1b with prototype-NS5A is interferon-resistant strain. The specific nature of these mutations would make it possible to develop the assays to predict interferon resistance.
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