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    A Mutation in the DNA Polymerase Accessory Factor of Herpes Simplex Virus 1 Restores Viral DNA Replication in the Presence of Raltegravir

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    Issue Date
    2014-10
    Author
    Zhou, Bin
    Yang, Kui
    Wills, Elizabeth
    Tang, Liang
    Baines, Joel D.
    Longnecker, R. M.
    Publisher
    American Society for Microbiology
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
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    Abstract
    Previous reports showed that raltegravir, a recently approved antiviral compound that targets HIV integrase, can inhibit the nuclease function of human cytomegalovirus (HCMV terminase) in vitro. In this study, subtoxic levels of raltegravir were shown to inhibit the replication of four different herpesviruses, herpes simplex virus 1 (HSV-1), HSV-2, HCMV, and mouse cytomegalovirus, by 30- to 700-fold, depending on the dose and the virus tested. Southern blotting and quantitative PCR revealed that raltegravir inhibits DNA replication of HSV-1 rather than cleavage of viral DNA. A raltegravir-resistant HSV-1 mutant was generated by repeated passage in the presence of 200 μM raltegravir. The genomic sequence of the resistant virus, designated clone 7, contained mutations in 16 open reading frames. Of these, the mutations F198S in unique long region 15 (UL15; encoding the large terminase subunit), A374V in UL32 (required for DNA cleavage and packaging), V296I in UL42 (encoding the DNA polymerase accessory factor), and A224S in UL54 (encoding ICP27, an important transcriptional regulator) were introduced independently into the wild-type HSV-1(F) genome, and the recombinant viruses were tested for raltegravir resistance. Viruses bearing both the UL15 and UL32 mutations inserted within the genome of the UL42 mutant were also tested. While the UL15, UL32, and UL54 mutant viruses were fully susceptible to raltegravir, any virus bearing the UL42 mutation was as resistant to raltegravir as clone 7. Overall, these results suggest that raltegravir may be a valuable therapeutic agent against herpesviruses and the antiviral activity targets the DNA polymerase accessory factor rather than the nuclease activity of the terminase.
    Description
    This is the published version. Copyright 2014 American Society for Microbiology
    URI
    http://hdl.handle.net/1808/19204
    DOI
    https://doi.org/10.1128/JVI.01540-14
    Collections
    • Molecular Biosciences Scholarly Works [573]
    Citation
    Zhou, B., K. Yang, E. Wills, L. Tang, and J. D. Baines. "A Mutation in the DNA Polymerase Accessory Factor of Herpes Simplex Virus 1 Restores Viral DNA Replication in the Presence of Raltegravir." Journal of Virology 88.19 (2014): 11121-1129. http://dx.doi.org/10.1128/JVI.01540-14

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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