A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir

Hepatitis C virus (HCV) genotype 3 presents a high level of both baseline and acquired resistance to direct-acting antivirals (DAAs), particularly those targeting the NS5A protein. To understand this resistance we studied a cohort of Brazilian patients treated with the NS5A DAA, daclatasvir and the...

Full description

Saved in:
Bibliographic Details
Published in:Journal of general virology 2021-01, Vol.102 (1)
Main Authors: Fernandes Campos, Guilherme Rodrigues, Ward, Joseph, Chen, Shucheng, Bittar, Cintia, Vilela Rodrigues, João Paulo, Martinelli, Ana de Lourdes Candolo, Souza, Fernanda Fernandes, Pereira, Leonardo Régis Leira, Rahal, Paula, Harris, Mark
Format: Article
Language:English
Subjects:
Antiviral Agents - pharmacology
Antiviral Agents - therapeutic use
Brazil
Carbamates - pharmacology
Carbamates - therapeutic use
Cell Line, Tumor
Cohort Studies
Drug Resistance, Viral - drug effects
Drug Resistance, Viral - genetics
Drug Therapy, Combination
Genotype
Hepacivirus - drug effects
Hepacivirus - genetics
Hepacivirus - physiology
Hepatitis C - drug therapy
Hepatitis C - virology
Humans
Imidazoles - pharmacology
Imidazoles - therapeutic use
Mutation
Pyrrolidines - pharmacology
Pyrrolidines - therapeutic use
Recurrence
Sofosbuvir - pharmacology
Sofosbuvir - therapeutic use
Valine - analogs & derivatives
Valine - pharmacology
Valine - therapeutic use
Viral Nonstructural Proteins - antagonists & inhibitors
Viral Nonstructural Proteins - genetics
Virus Replication - genetics
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Hepatitis C virus (HCV) genotype 3 presents a high level of both baseline and acquired resistance to direct-acting antivirals (DAAs), particularly those targeting the NS5A protein. To understand this resistance we studied a cohort of Brazilian patients treated with the NS5A DAA, daclatasvir and the nucleoside analogue, sofosbuvir. We observed a novel substitution at NS5A amino acid residue 98 [serine to glycine (S98G)] in patients who relapsed post-treatment. The effect of this substitution on both replication fitness and resistance to DAAs was evaluated using two genotype 3 subgenomic replicons. S98G had a modest effect on replication, but in combination with the previously characterized resistance-associated substitution (RAS), Y93H, resulted in a significant increase in daclatasvir resistance. This result suggests that combinations of substitutions may drive a high level of DAA resistance and provide some clues to the mechanism of action of the NS5A-targeting DAAs.
ISSN:0022-1317
1465-2099
DOI:10.1099/JGV.0.001496