Extinction of hepatitis C virus by ribavirin in hepatoma cells involves lethal mutagenesis.

Lethal mutagenesis, or virus extinction produced by enhanced mutation rates, is under investigation as an antiviral strategy that aims at counteracting the adaptive capacity of viral quasispecies, and avoiding selection of antiviral-escape mutants. To explore lethal mutagenesis of hepatitis C virus...

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Autores principales:	Ana M Ortega-Prieto, Julie Sheldon, Ana Grande-Pérez, Héctor Tejero, Josep Gregori, Josep Quer, Juan I Esteban, Esteban Domingo, Celia Perales
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a2aec13bd20841899de167897eb571b1
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spelling	oai:doaj.org-article:a2aec13bd20841899de167897eb571b12021-11-18T08:59:19ZExtinction of hepatitis C virus by ribavirin in hepatoma cells involves lethal mutagenesis.1932-620310.1371/journal.pone.0071039https://doaj.org/article/a2aec13bd20841899de167897eb571b12013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23976977/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Lethal mutagenesis, or virus extinction produced by enhanced mutation rates, is under investigation as an antiviral strategy that aims at counteracting the adaptive capacity of viral quasispecies, and avoiding selection of antiviral-escape mutants. To explore lethal mutagenesis of hepatitis C virus (HCV), it is important to establish whether ribavirin, the purine nucleoside analogue used in anti-HCV therapy, acts as a mutagenic agent during virus replication in cell culture. Here we report the effect of ribavirin during serial passages of HCV in human hepatoma Huh-7.5 cells, regarding viral progeny production and complexity of mutant spectra. Ribavirin produced an increase of mutant spectrum complexity and of the transition types associated with ribavirin mutagenesis, resulting in HCV extinction. Ribavirin-mediated depletion of intracellular GTP was not the major contributory factor to mutagenesis since mycophenolic acid evoked a similar decrease in GTP without an increase in mutant spectrum complexity. The intracellular concentration of the other nucleoside-triphosphates was elevated as a result of ribavirin treatment. Mycophenolic acid extinguished HCV without an intervening mutagenic activity. Ribavirin-mediated, but not mycophenolic acid-mediated, extinction of HCV occurred via a decrease of specific infectivity, a feature typical of lethal mutagenesis. We discuss some possibilities to explain disparate results on ribavirin mutagenesis of HCV.Ana M Ortega-PrietoJulie SheldonAna Grande-PérezHéctor TejeroJosep GregoriJosep QuerJuan I EstebanEsteban DomingoCelia PeralesPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 8, p e71039 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ana M Ortega-Prieto Julie Sheldon Ana Grande-Pérez Héctor Tejero Josep Gregori Josep Quer Juan I Esteban Esteban Domingo Celia Perales Extinction of hepatitis C virus by ribavirin in hepatoma cells involves lethal mutagenesis.
description	Lethal mutagenesis, or virus extinction produced by enhanced mutation rates, is under investigation as an antiviral strategy that aims at counteracting the adaptive capacity of viral quasispecies, and avoiding selection of antiviral-escape mutants. To explore lethal mutagenesis of hepatitis C virus (HCV), it is important to establish whether ribavirin, the purine nucleoside analogue used in anti-HCV therapy, acts as a mutagenic agent during virus replication in cell culture. Here we report the effect of ribavirin during serial passages of HCV in human hepatoma Huh-7.5 cells, regarding viral progeny production and complexity of mutant spectra. Ribavirin produced an increase of mutant spectrum complexity and of the transition types associated with ribavirin mutagenesis, resulting in HCV extinction. Ribavirin-mediated depletion of intracellular GTP was not the major contributory factor to mutagenesis since mycophenolic acid evoked a similar decrease in GTP without an increase in mutant spectrum complexity. The intracellular concentration of the other nucleoside-triphosphates was elevated as a result of ribavirin treatment. Mycophenolic acid extinguished HCV without an intervening mutagenic activity. Ribavirin-mediated, but not mycophenolic acid-mediated, extinction of HCV occurred via a decrease of specific infectivity, a feature typical of lethal mutagenesis. We discuss some possibilities to explain disparate results on ribavirin mutagenesis of HCV.
format	article
author	Ana M Ortega-Prieto Julie Sheldon Ana Grande-Pérez Héctor Tejero Josep Gregori Josep Quer Juan I Esteban Esteban Domingo Celia Perales
author_facet	Ana M Ortega-Prieto Julie Sheldon Ana Grande-Pérez Héctor Tejero Josep Gregori Josep Quer Juan I Esteban Esteban Domingo Celia Perales
author_sort	Ana M Ortega-Prieto
title	Extinction of hepatitis C virus by ribavirin in hepatoma cells involves lethal mutagenesis.
title_short	Extinction of hepatitis C virus by ribavirin in hepatoma cells involves lethal mutagenesis.
title_full	Extinction of hepatitis C virus by ribavirin in hepatoma cells involves lethal mutagenesis.
title_fullStr	Extinction of hepatitis C virus by ribavirin in hepatoma cells involves lethal mutagenesis.
title_full_unstemmed	Extinction of hepatitis C virus by ribavirin in hepatoma cells involves lethal mutagenesis.
title_sort	extinction of hepatitis c virus by ribavirin in hepatoma cells involves lethal mutagenesis.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/a2aec13bd20841899de167897eb571b1
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Extinction of hepatitis C virus by ribavirin in hepatoma cells involves lethal mutagenesis.

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