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dc.contributor.authorZhou, Bin
dc.contributor.authorYang, Kui
dc.contributor.authorWills, Elizabeth
dc.contributor.authorTang, Liang
dc.contributor.authorBaines, Joel D.
dc.contributor.authorLongnecker, R. M.
dc.date.accessioned2015-12-16T18:00:45Z
dc.date.available2015-12-16T18:00:45Z
dc.date.issued2014-10
dc.identifier.citationZhou, 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.01540-14en_US
dc.identifier.urihttp://hdl.handle.net/1808/19204
dc.descriptionThis is the published version. Copyright 2014 American Society for Microbiologyen_US
dc.description.abstractPrevious 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.en_US
dc.publisherAmerican Society for Microbiologyen_US
dc.titleA Mutation in the DNA Polymerase Accessory Factor of Herpes Simplex Virus 1 Restores Viral DNA Replication in the Presence of Raltegraviren_US
dc.typeArticle
kusw.kuauthorTang, Liang
kusw.kudepartmentMolecular Biosciencesen_US
dc.identifier.doi10.1128/JVI.01540-14
kusw.oaversionScholarly/refereed, publisher version
kusw.oapolicyThis item meets KU Open Access policy criteria.
dc.rights.accessrightsopenAccess


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