Skip to main content
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1989 May;33(5):635–640. doi: 10.1128/aac.33.5.635

Biological and biochemical characterization of clinical isolates of herpes simplex virus type 2 resistant to acyclovir.

N M Oliver 1, P Collins 1, J Van der Meer 1, J W Van't Wout 1
PMCID: PMC172504  PMID: 2546486

Abstract

A series of clinical isolates of herpes simplex virus type 2 were taken from a patient with chronic lymphocytic leukemia. Acyclovir (ACV) susceptibility assays revealed that some isolates were resistant to ACV and cross-resistant to ganciclovir but not to phosphonoacetic acid. The nature of the resistance was examined further. A number of cloned variants were generated, and thymidine kinase and DNA polymerase assays were carried out. Variants that were resistant to ACV were found to be thymidine kinase deficient. Evidence for alteration in the DNA polymerase was not found when ACV triphosphate or phosphonoacetic acid was used as the inhibitor. In vivo studies with the plaque-purified viruses showed that ACV resistance was associated with a reduced neurovirulence. In a zosteriform model, virus resistant to ACV was unable to induce secondary spread in the same dermatome, to invade the peripheral nervous system or the central nervous system, or to establish latent infections.

Full text

PDF
635

Selected References

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

  1. Barry D. W., Nusinoff-Lehrman S., Ellis M. N., Biron K. K., Furman P. A. Viral resistance, clinical experience. Scand J Infect Dis Suppl. 1985;47:155–164. [PubMed] [Google Scholar]
  2. Burns W. H., Saral R., Santos G. W., Laskin O. L., Lietman P. S., McLaren C., Barry D. W. Isolation and characterisation of resistant Herpes simplex virus after acyclovir therapy. Lancet. 1982 Feb 20;1(8269):421–423. doi: 10.1016/s0140-6736(82)91620-8. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Collins P., Appleyard G., Oliver N. M. Sensitivity of herpes virus isolates from acyclovir clinical trials. Am J Med. 1982 Jul 20;73(1A):380–382. doi: 10.1016/0002-9343(82)90127-9. [DOI] [PubMed] [Google Scholar]
  5. Collins P., Larder B. A., Oliver N. M., Kemp S., Smith I. W., Darby G. Characterization of a DNA polymerase mutant of herpes simplex virus from a severely immunocompromised patient receiving acyclovir. J Gen Virol. 1989 Feb;70(Pt 2):375–382. doi: 10.1099/0022-1317-70-2-375. [DOI] [PubMed] [Google Scholar]
  6. Collins P., Oliver N. M. Sensitivity monitoring of herpes simplex virus isolates from patients receiving acyclovir. J Antimicrob Chemother. 1986 Oct;18 (Suppl B):103–112. doi: 10.1093/jac/18.supplement_b.103. [DOI] [PubMed] [Google Scholar]
  7. Collins P. Viral sensitivity following the introduction of acyclovir. Am J Med. 1988 Aug 29;85(2A):129–134. [PubMed] [Google Scholar]
  8. Crumpacker C. S., Schnipper L. E., Marlowe S. I., Kowalsky P. N., Hershey B. J., Levin M. J. Resistance to antiviral drugs of herpes simplex virus isolated from a patient treated with acyclovir. N Engl J Med. 1982 Feb 11;306(6):343–346. doi: 10.1056/NEJM198202113060606. [DOI] [PubMed] [Google Scholar]
  9. Darby G., Field H. J., Salisbury S. A. Altered substrate specificity of herpes simplex virus thymidine kinase confers acyclovir-resistance. Nature. 1981 Jan 1;289(5793):81–83. doi: 10.1038/289081a0. [DOI] [PubMed] [Google Scholar]
  10. Dekker C., Ellis M. N., McLaren C., Hunter G., Rogers J., Barry D. W. Virus resistance in clinical practice. J Antimicrob Chemother. 1983 Sep;12 (Suppl B):137–152. doi: 10.1093/jac/12.suppl_b.137. [DOI] [PubMed] [Google Scholar]
  11. Ellis M. N., Barry D. W. Oral acyclovir therapy of genital herpes simplex virus type 2 infections in guinea pigs. Antimicrob Agents Chemother. 1985 Feb;27(2):167–171. doi: 10.1128/aac.27.2.167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fiddian A. P., Brigden D., Yeo J. M., Hickmott E. A. Acyclovir: an update of the clinical applications of this antiherpes agent. Antiviral Res. 1984 Jun;4(3):99–117. doi: 10.1016/0166-3542(84)90011-1. [DOI] [PubMed] [Google Scholar]
  13. Field H. J., Darby G. Pathogenicity in mice of strains of herpes simplex virus which are resistant to acyclovir in vitro and in vivo. Antimicrob Agents Chemother. 1980 Feb;17(2):209–216. doi: 10.1128/aac.17.2.209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. Hann I. M., Prentice H. G., Blacklock H. A., Ross M. G., Brigden D., Rosling A. E., Burke C., Crawford D. H., Brumfitt W., Hoffbrand A. V. Acyclovir prophylaxis against herpes virus infections in severely immunocompromised patients: randomised double blind trial. Br Med J (Clin Res Ed) 1983 Aug 6;287(6389):384–388. doi: 10.1136/bmj.287.6389.384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Klemperer H. G., Haynes G. R., Shedden W. I., Watson D. H. A virus-specific thymidine kinase in BHK-21 cells infected with herpes simplex virus. Virology. 1967 Jan;31(1):120–128. doi: 10.1016/0042-6822(67)90015-3. [DOI] [PubMed] [Google Scholar]
  17. Larder B. A., Darby G. Selection and characterisation of acyclovir-resistant herpes simplex virus type 1 mutants inducing altered DNA polymerase activities. Virology. 1985 Oct 30;146(2):262–271. doi: 10.1016/0042-6822(85)90009-1. [DOI] [PubMed] [Google Scholar]
  18. Lehrman S. N., Douglas J. M., Corey L., Barry D. W. Recurrent genital herpes and suppressive oral acyclovir therapy. Relation between clinical outcome and in-vitro drug sensitivity. Ann Intern Med. 1986 Jun;104(6):786–790. doi: 10.7326/0003-4819-104-6-786. [DOI] [PubMed] [Google Scholar]
  19. Lehrman S. N., Hill E. L., Rooney J. F., Ellis M. N., Barry D. W., Straus S. E. Extended acyclovir therapy for herpes genitalis: changes in virus sensitivity and strain variation. J Antimicrob Chemother. 1986 Oct;18 (Suppl B):85–94. doi: 10.1093/jac/18.supplement_b.85. [DOI] [PubMed] [Google Scholar]
  20. Maitland N. J., Smith I. W., Peutherer J. F., Robertson D. H., Jones K. W. Restriction endonuclease analysis of DNA from genital isolates of herpes simplex virus type 2. Infect Immun. 1982 Dec;38(3):834–842. doi: 10.1128/iai.38.3.834-842.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Parker A. C., Craig J. I., Collins P., Oliver N., Smith I. Acyclovir-resistant herpes simplex virus infection due to altered DNA polymerase. Lancet. 1987 Dec 19;2(8573):1461–1461. doi: 10.1016/s0140-6736(87)91157-3. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Sibrack C. D., Gutman L. T., Wilfert C. M., McLaren C., St Clair M. H., Keller P. M., Barry D. W. Pathogenicity of acyclovir-resistant herpes simplex virus type 1 from an immunodeficient child. J Infect Dis. 1982 Nov;146(5):673–682. doi: 10.1093/infdis/146.5.673. [DOI] [PubMed] [Google Scholar]
  24. Sibrack C. D., McLaren C., Barry D. W. Disease and latency characteristics of clinical herpes virus isolated after acyclovir therapy. Am J Med. 1982 Jul 20;73(1A):372–375. doi: 10.1016/0002-9343(82)90125-5. [DOI] [PubMed] [Google Scholar]
  25. Simmons A., Nash A. A. Zosteriform spread of herpes simplex virus as a model of recrudescence and its use to investigate the role of immune cells in prevention of recurrent disease. J Virol. 1984 Dec;52(3):816–821. doi: 10.1128/jvi.52.3.816-821.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Svennerholm B., Vahlne A., Löwhagen G. B., Widell A., Lycke E. Sensitivity of HSV strains isolated before and after treatment with acyclovir. Scand J Infect Dis Suppl. 1985;47:149–154. [PubMed] [Google Scholar]
  27. Tenser R. B., Miller R. L., Rapp F. Trigeminal ganglion infection by thymidine kinase-negative mutants of herpes simplex virus. Science. 1979 Aug 31;205(4409):915–917. doi: 10.1126/science.224454. [DOI] [PubMed] [Google Scholar]
  28. Wade J. C., McLaren C., Meyers J. D. Frequency and significance of acyclovir-resistant herpes simplex virus isolated from marrow transplant patients receiving multiple courses of treatment with acyclovir. J Infect Dis. 1983 Dec;148(6):1077–1082. doi: 10.1093/infdis/148.6.1077. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES