Extinction of zika virus and usutu virus by lethal mutagenesis reveals different patterns of sensitivity to three mutagenic drugs

Maria Rosaria Bassi, Raquel Navarro Sempere, Prashansa Meyn, Charlotta Polacek, Armando Arias*

*Corresponding author for this work

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    Abstract

    Flaviviruses constitute an increasing source of public health concern, with growing numbers of pathogens causing disease and geographic spread to temperate climates. Despite a large body of evidence supporting mutagenesis as a conceivable antiviral strategy, there are currently no data on the sensitivity to increased mutagenesis for Zika virus (ZIKV) and Usutu virus (USUV), two emerging flaviviral threats. In this study, we demonstrate that both viruses are sensitive to three ribonucleosides, favipiravir, ribavirin, and 5-fluorouracil, that have shown mutagenic activity against other RNA viruses while remaining unaffected by a mutagenic deoxyribonucleoside. Serial cell culture passages of ZIKV in the presence of these compounds resulted in the rapid extinction of infectivity, suggesting elevated sensitivity to mutagenesis. USUV extinction was achieved when a 10-fold dilution was applied between every passage, but not in experiments involving undiluted virus, indicating an overall lower susceptibility than ZIKV. Although the two viruses are inhibited by the same three drugs, ZIKV is relatively more susceptive to serial passage in the presence of purine analogues (favipiravir and ribavirin), while USUV replication is suppressed more efficiently by 5-fluorouracil. These differences in sensitivity typically correlate with the increases in the mutation frequencies observed in each nucleoside treatment. These results are relevant to the development of efficient therapies based on lethal mutagenesis and support the rational selection of different mutagenic nucleosides for each pathogen. We will discuss the implications of these results to the fidelity of flavivirus replication and the design of antiviral therapies based on lethal mutagenesis.
    Original languageEnglish
    Article numbere00380-18
    JournalAntimicrobial Agents and Chemotherapy
    Volume62
    Issue number9
    Number of pages15
    ISSN0066-4804
    DOIs
    Publication statusPublished - 2018

    Bibliographical note

    This is an openaccess article distributed under the terms of the Creative Commons Attribution 4.0 International license

    Keywords

    • 5-fluorouracil
    • Error threshold
    • Favipiravir
    • Flavivirus
    • Lethal mutagenesis
    • Mutation frequency
    • Ribavirin
    • Usutu virus
    • Zika virus

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