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Antiviral Agents

Lethal Mutagenesis of Rift Valley Fever Virus Induced by Favipiravir

Belén Borrego, Ana I. de Ávila, Esteban Domingo, Alejandro Brun
Belén Borrego
aCentro de Investigación en Sanidad Animal (CISA-INIA), Madrid, Spain
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Ana I. de Ávila
bCentro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Madrid, Spain
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Esteban Domingo
bCentro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Madrid, Spain
cCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, Madrid, Spain
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Alejandro Brun
aCentro de Investigación en Sanidad Animal (CISA-INIA), Madrid, Spain
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DOI: 10.1128/AAC.00669-19
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ABSTRACT

Rift Valley fever virus (RVFV) is an emerging, mosquito-borne, zoonotic pathogen with recurrent outbreaks taking a considerable toll in human deaths in many African countries, for which no effective treatment is available. In cell culture studies and with laboratory animal models, the nucleoside analogue favipiravir (T-705) has demonstrated great potential for the treatment of several seasonal, chronic, and emerging RNA virus infections in humans, suggesting applicability to control some viral outbreaks. Treatment with favipiravir was shown to reduce the infectivity of Rift Valley fever virus both in cell cultures and in experimental animal models, but the mechanism of this protective effect is not understood. In this work, we show that favipiravir at concentrations well below the toxicity threshold estimated for cells is able to extinguish RVFV from infected cell cultures. Nucleotide sequence analysis has documented RVFV mutagenesis associated with virus extinction, with a significant increase in G to A and C to U transition frequencies and a decrease of specific infectivity, hallmarks of lethal mutagenesis.

FOOTNOTES

    • Received 5 April 2019.
    • Returned for modification 23 April 2019.
    • Accepted 8 May 2019.
    • Accepted manuscript posted online 13 May 2019.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.00669-19.

  • Copyright © 2019 Borrego et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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Lethal Mutagenesis of Rift Valley Fever Virus Induced by Favipiravir
Belén Borrego, Ana I. de Ávila, Esteban Domingo, Alejandro Brun
Antimicrobial Agents and Chemotherapy Jul 2019, 63 (8) e00669-19; DOI: 10.1128/AAC.00669-19

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Lethal Mutagenesis of Rift Valley Fever Virus Induced by Favipiravir
Belén Borrego, Ana I. de Ávila, Esteban Domingo, Alejandro Brun
Antimicrobial Agents and Chemotherapy Jul 2019, 63 (8) e00669-19; DOI: 10.1128/AAC.00669-19
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KEYWORDS

favipiravir
Rift Valley fever virus
T-705
lethal mutagenesis

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