2018 Fiscal Year Final Research Report
Othello Hypothesis and 2-Hit Hypothesis Involved in the Development of HCV Strains Carrying RASs Manifesting Extreme Tolerance Against DAA Therapies.
| Project/Area Number |
16K09372
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Saitama Medical University |
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Principal Investigator |
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| Research Collaborator |
NAKAYAMA nobuhaki
UCHIDA yoshihito
UEMURA hayato
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | Hepatitis C virus / Direct-acting antivirals / RAS / NS5A複製複合体阻害薬 / NS5Bポリメラーゼ阻害薬 |
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| Outline of Final Research Achievements |
Hepatitis C virus (HCV) has been the most frequent etiology of hepatocellular carcinoma, but can be eradicated from the liver after antiviral therapies using direct-acting antivirals (DAAs). In a small part of patients, however, virologic failure develops during and after DAA therapies. First, we evaluated the mechanisms involved in the development of HCV strains carrying resistance-associated substitutions (RASs) in the NS5A region, and demonstrated the Othello failure involved in the development of virologic failure in patients without signature NS5A-RASs at baseline, and 2-hit failure associating occurrence of extremely severe tolerant HCV strains against NS5A replication complex inhibitors, such as NS5A-P32 deletion. Moreover, we found NS5B-A218S as a factor involved in derangement of antiviral efficacy of NS5A polymerase inhibitors, and nominated such phenomenon as Tom & Jerry failure.
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| Free Research Field |
消化器内科学
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| Academic Significance and Societal Importance of the Research Achievements |
DAAs治療不成功はNS5A-L31M/Y93Hで生じるが，これがない場合の不成功要因としてNS5A-L28M/R30Qを見出した。この置換は耐性でないが，耐性NS5A-L28M/R30Q/Y93Hが混在し，これが野生株と置換した（Othello現象）。一方，NS3/4Aプロテアーゼ阻害薬で不成功時には，NS5Aの塩基配列が変化し，NS5A複製複合体阻害薬投与後に高度耐性NS5A-P32欠損が発生した（2-ヒット現象）。一方，NS5Bポリメラーゼ阻害薬の効果はNS5B-A218Sによって減退することを見出した（Tom & Jerry現象）。これらの解明でRAS発生を防ぐ治療法確立に貢献した。
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