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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Microbiology Society
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116786/ https://www.ncbi.nlm.nih.gov/pubmed/33141008 http://dx.doi.org/10.1099/jgv.0.001496 |
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author | 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 |
author_facet | 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 |
author_sort | Fernandes Campos, Guilherme Rodrigues |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8116786 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Microbiology Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-81167862021-05-13 A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir 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 J Gen Virol Research Article 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. Microbiology Society 2020-11-03 /pmc/articles/PMC8116786/ /pubmed/33141008 http://dx.doi.org/10.1099/jgv.0.001496 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution. |
spellingShingle | Research Article 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 A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir |
title | A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir |
title_full | A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir |
title_fullStr | A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir |
title_full_unstemmed | A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir |
title_short | A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir |
title_sort | novel substitution in ns5a enhances the resistance of hepatitis c virus genotype 3 to daclatasvir |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116786/ https://www.ncbi.nlm.nih.gov/pubmed/33141008 http://dx.doi.org/10.1099/jgv.0.001496 |
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