Synergistic lethal mutagenesis of hepatitis C virus

Isabel Gallego, María Eugenia Soria, Josep Gregori, Ana I. de Ávila, Carlos García-Crespo, Elena Moreno, Ignacio Gadea, Jaime Esteban, Ricardo Fernández-Roblas, Juan Ignacio Esteban, Jordi Gómez, Josep Quer, Esteban Domingo*, Celia Perales

*Autor correspondiente de este trabajo

Producción científica: Contribución a una revistaArtículoInvestigaciónrevisión exhaustiva

12 Citas (Scopus)

Resumen

Lethal mutagenesis is an antiviral approach that consists of extinguishing a virus by an excess of mutations acquired during replication in the presence of a mutagenic agent, often a nucleotide analogue. One of its advantages is its broad-spectrum nature, which renders the strategy potentially effective against emergent RNA viral infections. Here we describe the synergistic lethal mutagenesis of hepatitis C virus (HCV) by a combination of favipiravir (T-705) and ribavirin. Synergy has been documented over a broad range of analogue concentrations using the Chou-Talalay method implemented in CompuSyn graphics software, with the average dose reduction index (DRI) being above 1 (68.02 ± 101.6 for favipiravir and 5.83 ± 6.07 for ribavirin) and the average combination indices (CI) being below 1 (0.52 ± 0.28). Furthermore, analogue concentrations that individually did not extinguish high-fitness HCV in 10 serial infections extinguished high-fitness HCV in 1 to 2 passages when used in combination. Although both analogues displayed a preference for G ¡ A and C ¡ U transitions, deep sequencing analysis of mutant spectra indicated a different preference of the two analogues for the mutation sites, thus unveiling a new possible synergy mechanism in lethal mutagenesis. The prospects for synergy among mutagenic nucleotides as a strategy to confront emerging viral infections are discussed.
Idioma originalInglés
Número de artículoe01653-19
Número de páginas13
PublicaciónAntimicrobial Agents and Chemotherapy
Volumen63
N.º12
DOI
EstadoPublicada - 21 nov 2019

Palabras clave

  • Favipiravir
  • Ribavirin
  • Viral quasispecies
  • Antiviral therapy

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