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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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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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 / HCV / DAA / NS5A / NS5B / NS5A複製複合体 / NS5Bポリメラーゼ / Bioinformatics / Deep sequencing / 肝臓学 / 内科 / ウイルス / 薬剤反応性 |
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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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| 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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Report
(4 results)
Research Products
(30 results)
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[Journal Article] A case of genotype-3b HCV in which whole-genome was successfully analyzed using third-generation nanopore sequencing.2019
Author(s)
Uchida Y, Kouyama JI, Naiki K, Uemura H, Tsuji S, Sugawara K, Nakao M, Motoya D, Nakayama N, Imai Y, Tomiya T, Mochida S.
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Journal Title
Hepatol Res
Volume: in press
Issue: 9
Pages: 1083-1087
DOI
Related Report
Peer Reviewed
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[Journal Article] NS5A-P32 deletion as a factor involved in virologic failure in patients receiving glecaprevir and pibrentasvir.2019
Author(s)
Umemura J, Uchida Y, Koutyama JI, Naiki K, Tsuji S, Sugawara K, Nakao M, Motoya D, Nakayama N, Imai Y, Tomiya T, Mochida S
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Journal Title
J Gastroenterol
Volume: in press
Issue: 5
Pages: 459-470
DOI
Related Report
Peer Reviewed
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[Journal Article] Serum asunaprevir concentrations showing correklation with th extent of liver fibrosis as a factor inducing liver injuries in patients with genotype-1b hepattis C virus receiving daclatasvir plus asunaprevir therapy.2018
Author(s)
Uchida Y, Naiki K, Kouyama JI, Sugawara K, Nakao M, Motoya D, Inao M, Nakayama N, Imai Y, Tomiya T, Mochida S
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Journal Title
PLoS One
Volume: 13 (10)
Issue: 10
Pages: e0205600-e0205600
DOI
Related Report
Peer Reviewed
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[Journal Article] Significance of NS5B substitutions in genotype 1b hepatitis C virus evaluated by bioinformatics analysis.2018
Author(s)
Uchida Y, Nakamura S, Kouyama J, Naiki K, Motoya D, Sigawara K, Inao M, Imai Y, Nakayama N, Tomiya T, Hedskog C, Brainard D, Mo H, Mochida S
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Journal Title
Sci Rep
Volume: 8 (1)
Issue: 1
Pages: 8818-8818
DOI
Related Report
Peer Reviewed
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[Journal Article] Significance of variants associated with resistance to NS5A inhibitors in Japanese patients with genotype 1b hepatitis C virus infection as evaluated using cycling-probe real-time PCR combined with direct sequencing.2016
Author(s)
Uchida Y, Kouyama J, Naiki K, Sugawara K, Ando S, Nakaoa M, Motoya D, Inao M, Imai Y, Nakayama N, Mochida S.
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Journal Title
J Gastroenterol
Volume: 51
Pages: 260-270
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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