Skip to main content
Journal of Virology logoLink to Journal of Virology
. 1981 Dec;40(3):936–941. doi: 10.1128/jvi.40.3.936-941.1981

Acyclovir-resistant mutants of herpes simplex virus type 1 express altered DNA polymerase or reduced acyclovir phosphorylating activities.

P A Furman, D M Coen, M H St Clair, P A Schaffer
PMCID: PMC256706  PMID: 6275127

Abstract

The biochemical properties of four acyclovir-resistant mutants are described. Two of these mutants, PAAr5 and BWr, specified nucleotidyl transferase (DNA polymerase) activities which were less sensitive to inhibition by acyclovir triphosphate than their wild-type counterparts. Another mutant, IUdRr, exhibited reduced ability to phosphorylate acyclovir. The fourth mutant, ACGr4, both induced an altered DNA polymerase and failed to phosphorylate appreciable amounts of acyclovir. BWr, a new acyclovir-resistant mutant derived from the Patton strain of herpes simplex virus type 1, induced a DNA polymerase resistant to inhibition by acyclovir triphosphate, but, unlike the polymerases induced by PAAr5 and ACGr4, still sensitive to phosphonoacetic acid. Resistance of BWr to acyclovir mapped close to the PAAr locus and was separable from mutations in the herpes simplex virus thymidine kinase gene by recombination analysis.

Full text

PDF
936

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aron G. M., Purifoy D. J., Schaffer P. A. DNA synthesis and DNA polymerase activity of herpes simplex virus type 1 temperature-sensitive mutants. J Virol. 1975 Sep;16(3):498–507. doi: 10.1128/jvi.16.3.498-507.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chartrand P., Crumpacker C. S., Schaffer P. A., Wilkie N. M. Physical and genetic analysis of the herpes simplex virus DNA polymerase locus. Virology. 1980 Jun;103(2):311–326. doi: 10.1016/0042-6822(80)90190-7. [DOI] [PubMed] [Google Scholar]
  3. Chartrand P., Stow N. D., Timbury M. C., Wilkie N. M. Physical mapping of paar mutations of herpes simplex virus type 1 and type 2 by intertypic marker rescue. J Virol. 1979 Aug;31(2):265–276. doi: 10.1128/jvi.31.2.265-276.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Coen D. M., Schaffer P. A. Two distinct loci confer resistance to acycloguanosine in herpes simplex virus type 1. Proc Natl Acad Sci U S A. 1980 Apr;77(4):2265–2269. doi: 10.1073/pnas.77.4.2265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Collins P., Bauer D. J. Relative potencies of anti-herpes compounds. Ann N Y Acad Sci. 1977 Mar 4;284:49–59. doi: 10.1111/j.1749-6632.1977.tb21936.x. [DOI] [PubMed] [Google Scholar]
  6. Crumpacker C. S., Chartrand P., Subak-Sharpe J. H., Wilkie N. M. Resistance of herpes simplex virus to acycloguanosine--genetic and physical analysis. Virology. 1980 Aug;105(1):171–184. doi: 10.1016/0042-6822(80)90165-8. [DOI] [PubMed] [Google Scholar]
  7. Elion G. B., Furman P. A., Fyfe J. A., de Miranda P., Beauchamp L., Schaeffer H. J. Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5716–5720. doi: 10.1073/pnas.74.12.5716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Field H. J., Darby G., Wildy P. Isolation and characterization of acyclovir-resistant mutants of herpes simplex virus. J Gen Virol. 1980 Jul;49(1):115–124. doi: 10.1099/0022-1317-49-1-115. [DOI] [PubMed] [Google Scholar]
  9. Furman P. A., McGuirt P. V., Keller P. M., Fyfe J. A., Elion G. B. Inhibition by acyclovir of cell growth and DNA synthesis of cells biochemically transformed with herpesvirus genetic information. Virology. 1980 Apr 30;102(2):420–430. doi: 10.1016/0042-6822(80)90109-9. [DOI] [PubMed] [Google Scholar]
  10. Furman P. A., St Clair M. H., Fyfe J. A., Rideout J. L., Keller P. M., Elion G. B. Inhibition of herpes simplex virus-induced DNA polymerase activity and viral DNA replication by 9-(2-hydroxyethoxymethyl)guanine and its triphosphate. J Virol. 1979 Oct;32(1):72–77. doi: 10.1128/jvi.32.1.72-77.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fyfe J. A., Keller P. M., Furman P. A., Miller R. L., Elion G. B. Thymidine kinase from herpes simplex virus phosphorylates the new antiviral compound, 9-(2-hydroxyethoxymethyl)guanine. J Biol Chem. 1978 Dec 25;253(24):8721–8727. [PubMed] [Google Scholar]
  12. Hay J., Moss H., Jamieson A. T., Timbury M. C. Herpesvirus proteins: DNA polymerase and pyrimidine deoxynucleoside kinase activities in temperature-sensitive mutants of herpes simplex virus type 2. J Gen Virol. 1976 Apr;31(1):65–73. doi: 10.1099/0022-1317-31-1-65. [DOI] [PubMed] [Google Scholar]
  13. Hay J., Subak-Sharpe J. H. Mutants of herpes simplex virus types 1 and 2 that are resistant to phosphonoacetic acid induce altered DNA polymerase activities in infected cells. J Gen Virol. 1976 Apr;31(1):145–148. doi: 10.1099/0022-1317-31-1-145. [DOI] [PubMed] [Google Scholar]
  14. Honess R. W., Watson D. H. Herpes simplex virus resistance and sensitivity to phosphonoacetic acid. J Virol. 1977 Feb;21(2):584–600. doi: 10.1128/jvi.21.2.584-600.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jofre J. T., Schaffer P. A., Parris D. S. Genetics of resistance to phosphonoacetic acid in strain KOS of herpes simplex virus type 1. J Virol. 1977 Sep;23(3):833–836. doi: 10.1128/jvi.23.3.833-836.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kornberg A. Active center of DNA polymerase. Science. 1969 Mar 28;163(3874):1410–1418. doi: 10.1126/science.163.3874.1410. [DOI] [PubMed] [Google Scholar]
  17. Mao J. C., Robishaw E. E., Overby L. R. Inhibition of DNA polymerase from herpes simplex virus-infected wi-38 cells by phosphonoacetic Acid. J Virol. 1975 May;15(5):1281–1283. doi: 10.1128/jvi.15.5.1281-1283.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Miller R. L., Rapp F. Distinguishing cytomegalovirus, mycoplasma, and cellular DNA polymerases. J Virol. 1976 Dec;20(3):564–569. doi: 10.1128/jvi.20.3.564-569.1976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Miller W. H., Miller R. L. Phosphorylation of acyclovir (acycloguanosine) monophosphate by GMP kinase. J Biol Chem. 1980 Aug 10;255(15):7204–7207. [PubMed] [Google Scholar]
  20. Parris D. S., Dixon R. A., Schaffer P. A. Physical mapping of herpes simplex virus type 1 ts mutants by marker rescue: correlation of the physical and genetic maps. Virology. 1980 Jan 30;100(2):275–287. doi: 10.1016/0042-6822(80)90519-x. [DOI] [PubMed] [Google Scholar]
  21. Purifoy D. J., Lewis R. B., Powell K. L. Identification of the herpes simplex virus DNA polymerase gene. Nature. 1977 Oct 13;269(5629):621–623. doi: 10.1038/269621a0. [DOI] [PubMed] [Google Scholar]
  22. Purifoy D. J., Powell K. L. Herpes simplex virus DNA polymerase as the site of phosphonoacetate sensitivity: temperature-sensitive mutants. J Virol. 1977 Nov;24(2):470–477. doi: 10.1128/jvi.24.2.470-477.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Schaeffer H. J., Beauchamp L., de Miranda P., Elion G. B., Bauer D. J., Collins P. 9-(2-hydroxyethoxymethyl) guanine activity against viruses of the herpes group. Nature. 1978 Apr 13;272(5654):583–585. doi: 10.1038/272583a0. [DOI] [PubMed] [Google Scholar]
  24. Schaffer P. A., Tevethia M. J., Benyesh-Melnick M. Recombination between temperature-sensitive mutants of herpes simplex virus type 1. Virology. 1974 Mar;58(1):219–228. doi: 10.1016/0042-6822(74)90156-1. [DOI] [PubMed] [Google Scholar]
  25. Schnipper L. E., Crumpacker C. S. Resistance of herpes simplex virus to acycloguanosine: role of viral thymidine kinase and DNA polymerase loci. Proc Natl Acad Sci U S A. 1980 Apr;77(4):2270–2273. doi: 10.1073/pnas.77.4.2270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Smith K. O., Kennell W. L., Poirier R. H., Lynd F. T. In vitro and in vivo resistance of herpes simplex virus to 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine). Antimicrob Agents Chemother. 1980 Feb;17(2):144–150. doi: 10.1128/aac.17.2.144. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Weissbach A., Hong S. C., Aucker J., Muller R. Characterization of herpes simplex virus-induced deoxyribonucleic acid polymerase. J Biol Chem. 1973 Sep 25;248(18):6270–6277. [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES