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Identifying Different Mutation Sites Leading to Resistance to the Direct-Acting Antiviral (DAA) Sofosbuvir in Hepatitis C Virus Patients from Egypt

The hepatitis C virus (HCV) is a major global health challenge and a leading cause of morbidity and mortality. Many direct-acting antivirals (DAAs) target essential macromolecules involved in the virus’ life cycle. Although such DAAs achieve great success in reducing the viral load in genotype 1 inf...

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Autores principales: Shoun, Aly Atef, Abozahra, Rania, Baraka, Kholoud, Mehrez, Mai, Abdelhamid, Sarah M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9024585/
https://www.ncbi.nlm.nih.gov/pubmed/35456731
http://dx.doi.org/10.3390/microorganisms10040679
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author Shoun, Aly Atef
Abozahra, Rania
Baraka, Kholoud
Mehrez, Mai
Abdelhamid, Sarah M.
author_facet Shoun, Aly Atef
Abozahra, Rania
Baraka, Kholoud
Mehrez, Mai
Abdelhamid, Sarah M.
author_sort Shoun, Aly Atef
collection PubMed
description The hepatitis C virus (HCV) is a major global health challenge and a leading cause of morbidity and mortality. Many direct-acting antivirals (DAAs) target essential macromolecules involved in the virus’ life cycle. Although such DAAs achieve great success in reducing the viral load in genotype 1 infections, other genotypes demonstrate different levels of response. This study focused on mutation sites associated with patients with genotype 4a infections that failed to respond to treatment with sofosbuvir. The genotyping of HCV samples from patients with virological failure, and responder patients, was conducted using Geno2Pheno webserver-based full NS5B sequences. We constructed 3D structural models for all the samples and used structural analysis to investigate the effect of amino acid substitution on the observed resistance to SOF-based treatment, and the docking of sofosbuvir into the active sites of the 10 models was performed. Finally, 10 molecular dynamic (MD) simulation experiments were conducted to compare the stability of the 3D models of the resistant samples against the stability of the 3D models of the responder samples. The results highlighted the presence of HCV subtype 4a in all ten samples; in addition, an amino acid (aa) substitution in the palm region may hinder HCV polymerase activity. In this study, we provide evidence that a mutation in the NS5B gene that induces resistance to sofosbuvir in patients with the S282T/C/R mutant virus is present in the Egyptian population. Overall, the docking and MD results support our findings and highlight the significant impact of the identified mutations on the resistance of HCV NS5B RNA-dependent RNA polymerase to direct-acting antivirals (DAAs).
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spelling pubmed-90245852022-04-23 Identifying Different Mutation Sites Leading to Resistance to the Direct-Acting Antiviral (DAA) Sofosbuvir in Hepatitis C Virus Patients from Egypt Shoun, Aly Atef Abozahra, Rania Baraka, Kholoud Mehrez, Mai Abdelhamid, Sarah M. Microorganisms Article The hepatitis C virus (HCV) is a major global health challenge and a leading cause of morbidity and mortality. Many direct-acting antivirals (DAAs) target essential macromolecules involved in the virus’ life cycle. Although such DAAs achieve great success in reducing the viral load in genotype 1 infections, other genotypes demonstrate different levels of response. This study focused on mutation sites associated with patients with genotype 4a infections that failed to respond to treatment with sofosbuvir. The genotyping of HCV samples from patients with virological failure, and responder patients, was conducted using Geno2Pheno webserver-based full NS5B sequences. We constructed 3D structural models for all the samples and used structural analysis to investigate the effect of amino acid substitution on the observed resistance to SOF-based treatment, and the docking of sofosbuvir into the active sites of the 10 models was performed. Finally, 10 molecular dynamic (MD) simulation experiments were conducted to compare the stability of the 3D models of the resistant samples against the stability of the 3D models of the responder samples. The results highlighted the presence of HCV subtype 4a in all ten samples; in addition, an amino acid (aa) substitution in the palm region may hinder HCV polymerase activity. In this study, we provide evidence that a mutation in the NS5B gene that induces resistance to sofosbuvir in patients with the S282T/C/R mutant virus is present in the Egyptian population. Overall, the docking and MD results support our findings and highlight the significant impact of the identified mutations on the resistance of HCV NS5B RNA-dependent RNA polymerase to direct-acting antivirals (DAAs). MDPI 2022-03-22 /pmc/articles/PMC9024585/ /pubmed/35456731 http://dx.doi.org/10.3390/microorganisms10040679 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Shoun, Aly Atef
Abozahra, Rania
Baraka, Kholoud
Mehrez, Mai
Abdelhamid, Sarah M.
Identifying Different Mutation Sites Leading to Resistance to the Direct-Acting Antiviral (DAA) Sofosbuvir in Hepatitis C Virus Patients from Egypt
title Identifying Different Mutation Sites Leading to Resistance to the Direct-Acting Antiviral (DAA) Sofosbuvir in Hepatitis C Virus Patients from Egypt
title_full Identifying Different Mutation Sites Leading to Resistance to the Direct-Acting Antiviral (DAA) Sofosbuvir in Hepatitis C Virus Patients from Egypt
title_fullStr Identifying Different Mutation Sites Leading to Resistance to the Direct-Acting Antiviral (DAA) Sofosbuvir in Hepatitis C Virus Patients from Egypt
title_full_unstemmed Identifying Different Mutation Sites Leading to Resistance to the Direct-Acting Antiviral (DAA) Sofosbuvir in Hepatitis C Virus Patients from Egypt
title_short Identifying Different Mutation Sites Leading to Resistance to the Direct-Acting Antiviral (DAA) Sofosbuvir in Hepatitis C Virus Patients from Egypt
title_sort identifying different mutation sites leading to resistance to the direct-acting antiviral (daa) sofosbuvir in hepatitis c virus patients from egypt
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9024585/
https://www.ncbi.nlm.nih.gov/pubmed/35456731
http://dx.doi.org/10.3390/microorganisms10040679
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