Determination and therapeutic exploitation of Ebola virus spontaneous mutation frequency

Kendra J. Alfson, Gabriella Worwa, Ricardo Carrion, Anthony Griffiths

    Research output: Contribution to journalArticlepeer-review

    9 Scopus citations

    Abstract

    Ebola virus (EBOV) is an RNA virus that can cause hemorrhagic fever with high fatality rates, and there are no approved vaccines or therapies. Typically, RNA viruses have high spontaneous mutation rates, which permit rapid adaptation to selection pressures and have other important biological consequences. However, it is unknown if filoviruses exhibit high mutation frequencies. Ultradeep sequencing and a recombinant EBOV that carries the gene encoding green fluorescent protein were used to determine the spontaneous mutation frequency of EBOV. The effects of the guanosine analogue ribavirin during EBOV infections were also assessed. Ultradeep sequencing revealed that the mutation frequency for EBOV was high and similar to those of other RNA viruses. Interestingly, significant genetic diversity was not observed in viable viruses, implying that changes were not well tolerated. We hypothesized that this could be exploited therapeutically. In vitro, the presence of ribavirin increased the error rate, and the 50% inhibitory concentration (IC50) was 27 μM. In a mouse model of ribavirin therapy given pre-EBOV exposure, ribavirin treatment corresponded with a significant delay in time to death and up to 75% survival. In mouse and monkey models of therapy given post-EBOV exposure, ribavirin treatment also delayed the time to death and increased survival. These results demonstrate that EBOV has a spontaneous mutation frequency similar to those of other RNA viruses. These data also suggest a potential for therapeutic use of ribavirin for human EBOV infections.

    Original languageEnglish (US)
    Pages (from-to)2345-2355
    Number of pages11
    JournalJournal of virology
    Volume90
    Issue number5
    DOIs
    StatePublished - 2016

    ASJC Scopus subject areas

    • Microbiology
    • Immunology
    • Insect Science
    • Virology

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