A Mutation in the DNA Polymerase Accessory Factor of Herpes Simplex Virus 1 Restores Viral DNA Replication in the Presence of Raltegravir
| Autor: | Elizabeth G. Wills, Joel D. Baines, Bin Zhou, Liang Tang, Kui Yang |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
DNA Replication
Gene Expression Regulation Viral Models Molecular Human cytomegalovirus Muromegalovirus Transcription Genetic DNA polymerase Herpesvirus 2 Human viruses Immunology Cytomegalovirus DNA-Directed DNA Polymerase Herpesvirus 1 Human medicine.disease_cause Antiviral Agents Microbiology Virus Cell Line Raltegravir Potassium Mice Viral Proteins Virology Vaccines and Antiviral Agents Chlorocebus aethiops Drug Resistance Viral medicine Animals Humans biology DNA replication medicine.disease Raltegravir Molecular biology Pyrrolidinones Integrase Exodeoxyribonucleases Herpes simplex virus Insect Science DNA Viral Mutation biology.protein medicine.drug |
| Zdroj: | Journal of Virology. 88:11121-11129 |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.01540-14 |
| Popis: | 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 (U L 15; encoding the large terminase subunit), A374V in U L 32 (required for DNA cleavage and packaging), V296I in U L 42 (encoding the DNA polymerase accessory factor), and A224S in U L 54 (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 U L 15 and U L 32 mutations inserted within the genome of the U L 42 mutant were also tested. While the U L 15, U L 32, and U L 54 mutant viruses were fully susceptible to raltegravir, any virus bearing the U L 42 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. IMPORTANCE This paper shows that raltegravir, the antiretrovirus drug targeting integrase, is effective against various herpesviruses. Drug resistance mapped to the herpesvirus DNA polymerase accessory factor, which was an unexpected finding. |
| Databáze: | OpenAIRE |
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