Effects of resistance-associated variants in genotype 2 hepatitis C virus on viral replication and susceptibility to antihepatitis C virus drugs.
NS5A F28S/M31I
NS5B S282 T
genotype 2
hepatitis C virus
resistant-associated variant
Journal
Hepatology research : the official journal of the Japan Society of Hepatology
ISSN: 1386-6346
Titre abrégé: Hepatol Res
Pays: Netherlands
ID NLM: 9711801
Informations de publication
Date de publication:
Nov 2019
Nov 2019
Historique:
received:
06
05
2019
revised:
14
06
2019
accepted:
23
06
2019
pubmed:
2
7
2019
medline:
2
7
2019
entrez:
2
7
2019
Statut:
ppublish
Résumé
Development of direct-acting antivirals (DAAs) has made antihepatitis C virus (HCV) treatment highly safe and effective. However, the emergence of resistant-associated variants (RAVs) after failure of DAA therapy affects retreatment outcomes. In particular, genotype 1 HCV with P32 deletion has been reported to be highly resistant to all approved non-structural protein (NS)5A inhibitors. However, analysis of RAVs in genotype 2 HCV has been limited. Accordingly, in this study, we evaluated the roles of genotype 2 HCV variants in antiviral drug efficacy. We utilized HCV-2b/2a (JFH-1) chimeric virus (genotype 2a), which replicates more robustly than JFH-1. We constructed various genotype 2a JFH-1-based HCV cell culture systems with NS3 (D168E), NS5A (F28S, F28S/M31I, P32 deletion, and Y93H), and NS5B (S282 T) RAVs and analyzed the replication ability and sensitivity to various anti-HCV reagents. Genotype 2a-based HCV with NS5A-P32 deletion could not replicate even in long-term cultures. Genotype 2a-based HCV with NS5A-F28S/M31I showed significantly higher replication ability than the wild-type strain, and replication could not be suppressed, even with high concentrations of NS5A inhibitors, including pibrentasvir and velpatasvir (<1000-10 000 fold-resistance compared with the wild-type strain). However, genotype 2a-based HCV with NA5A-F28S/M31I was sensitive to HCV protease inhibitor, NS5B inhibitor, interferon-α, and ribavirin. Genotype 2a-based HCV with NS5B-S282 T was resistant to sofosbuvir, but was highly sensitive to ribavirin compared with the control. When undertaking retreatment for genotype 2a HCV-infected patients who fail to respond to DAAs, the optimized retreatment should be chosen according to the sensitivity of the emerging RAVs to anti-HCV drugs.
Types de publication
Journal Article
Langues
eng
Pagination
1275-1285Subventions
Organisme : KAKENHI
ID : 19 K08458
Organisme : Japan Society for the Promotion of Science KAKENHI
Organisme : Japan Agency for Medical Research and Development
ID : 19fk0210047s0401
Organisme : Japan Agency for Medical Research and Development
ID : 19fk0210058h0001
Organisme : Japan Agency for Medical Research and Development
ID : 19fk0210048s0501
Organisme : Japan Agency for Medical Research and Development
ID : 19fk0310101s0503
Organisme : Japan Agency for Medical Research and Development
ID : 19fk0210018h0003
Organisme : Japan Agency for Medical Research and Development
ID : 19fk0210022h0103
Organisme : Japan Agency for Medical Research and Development
ID : 19fk0210022h0103, 19fk0210018h0003, 19fk0310101s05
Informations de copyright
© 2019 The Japan Society of Hepatology.
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