@article{a64c30524a5e4e7fa26ef972059eb80b,
title = "Synergistic lethal mutagenesis of hepatitis C virus",
abstract = "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.",
keywords = "Favipiravir, Ribavirin, Viral quasispecies, Antiviral therapy, Favipiravir, Ribavirin, Viral quasispecies, Antiviral therapy, Favipiravir, Ribavirin, Viral quasispecies, Antiviral therapy",
author = "Isabel Gallego and Soria, {Mar{\'i}a Eugenia} and Josep Gregori and {de {\'A}vila}, {Ana I.} and Carlos Garc{\'i}a-Crespo and Elena Moreno and Ignacio Gadea and Jaime Esteban and Ricardo Fern{\'a}ndez-Roblas and Esteban, {Juan Ignacio} and Jordi G{\'o}mez and Josep Quer and Esteban Domingo and Celia Perales",
note = "Funding Information: C.P. is supported by the Miguel Servet program of the Instituto de Salud Carlos III (grant CP14/00121), cofinanced by the European Regional Development Fund (ERDF). The Centro de Investigaci{\'o}n en Red de Enfermedades Hep{\'a}ticas y Digestivas (CIBERehd) is funded by the Instituto de Salud Carlos III. The work in Madrid, Spain, was supported by grant SAF2014-52400-R from the Ministerio de Econom{\'i}a y Competitividad, grants SAF2017-87846-R, BFU2017-91384-EXP, and PI18/00210 from the Ministerio de Ciencia, Innovaci{\'o}n y Universidades, grant S2013/ABI-2906 from PLATESA from the Comunidad de Madrid/ FEDER, and grant P2018/BAA-4370 from PLATESA2 from the Comunidad de Madrid/FEDER. The work in Barcelona, Spain, was also funded by the Instituto de Salud Carlos III; by grant PI16/00337, cofinanced by the European Regional Development Fund (ERDF); and by the Centro para el Desarrollo Tecnol{\'o}gico Industrial (CDTI), Spanish Ministry of Economics and Competitiveness (MINECO) (grant IDI-20151125). Institutional grants from the Fundaci{\'o}n Ram{\'o}n Areces and Banco Santander to CBMSO are also acknowledged. Publisher Copyright: Copyright {\textcopyright} 2019 American Society for Microbiology. All Rights Reserved.",
year = "2019",
month = nov,
day = "21",
doi = "10.1128/AAC.01653-19",
language = "English",
volume = "63",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "12",
}