1887

Abstract

A panel of 10 clinical isolates of herpes simplex virus (HSV) deficient in the expression of thymidine kinase (TK) and phenotypically resistant to aciclovir was characterized. Sequence analysis revealed a variety of mutations in TK (nucleotide substitutions, insertions and deletions), most of which resulted in truncated TK polypeptides. In line with previous reports, the most common mutation was a single G insertion in the ‘G-string’ motif. One HSV-1 isolate and two HSV-2 isolates appeared to encode full-length polypeptides and, in each case, an amino acid substitution likely to be responsible for the phenotype was identified. Pathogenicity was determined using a zosteriform model of HSV infection in BALB/c mice. The majority of isolates appeared to show impaired growth at the inoculation site compared with wild-type virus. They also showed poor replication in the peripheral nervous system and little evidence of zosteriform spread. One exception was isolate 4, which had a double G insertion in the G-string but, nevertheless, exhibited zosteriform spread. These studies confirmed that TK-deficient viruses display a range of neurovirulence with respect to latency and zosteriform spread. These results are discussed in the light of previous experience with TK-deficient viruses.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.18880-0
2003-06-01
2024-04-18
Loading full text...

Full text loading...

/deliver/fulltext/jgv/84/6/vir841393.html?itemId=/content/journal/jgv/10.1099/vir.0.18880-0&mimeType=html&fmt=ahah

References

  1. Blyth W. A., Harbour D. A., Hill T. J. 1984; Pathogenesis of zosteriform spread of herpes simplex virus in the mouse. J Gen Virol 65:1477–1486
    [Google Scholar]
  2. Brown D. G., Visse R., Sandhu G., Davies A., Rizkallah P. J., Melitz C., Summers W. C., Sanderson M. R. 1995; Crystal structures of the thymidine kinase from herpes simplex virus type-1 in complex with deoxythymidine and ganciclovir. Nat Struct Biol 2:876–881
    [Google Scholar]
  3. Christophers J., Clayton J., Craske J., Ward R., Collins P., Trowbridge M., Darby G. 1998; Survey of resistance of herpes simplex virus to acyclovir in northwest England. Antimicrob Agents Chemother 42:868–872
    [Google Scholar]
  4. Coen D. M., Schaffer P. A. 1980; Two distinct loci confer resistance to acycloguanosine in herpes simplex virus type 1. Proc Natl Acad Sci U S A 77:2265–2269
    [Google Scholar]
  5. Coen D. M., Irmiere A. F., Jacobson J. G., Kerns K. M. 1989; Low levels of herpes simplex virus thymidine-thymidylate kinase are not limiting for sensitivity to certain antiviral drugs or for latency in a mouse model. Virology 168:221–231
    [Google Scholar]
  6. Collins P., Oliver N. M. 1986; Sensitivity monitoring of herpes simplex virus isolates from patients receiving acyclovir. J Antimicrob Chemother 18 (Suppl. B):103–112
    [Google Scholar]
  7. Collins P., Darby G. 1991; Laboratory studies of herpes simplex virus strains resistant to acyclovir. Rev Med Virol 1:19–28
    [Google Scholar]
  8. Collins P., Ellis M. N. 1993; Sensitivity monitoring of clinical isolates of herpes simplex virus to acyclovir. J Med Virol (Suppl) 1:58–66
    [Google Scholar]
  9. Collins P., Appleyard G. A., Oliver N. M. 1982; Sensitivity of herpes virus isolates from acyclovir clinical trials. Am J Med 73:380–382
    [Google Scholar]
  10. Darby G., Larder B. A., Inglis M. M. 1986; Evidence that the ‘active centre’ of the herpes simplex virus thymidine kinase involves an interaction between three distinct regions of the polypeptide. J Gen Virol 67:753–758
    [Google Scholar]
  11. Efstathiou S., Kemp S., Darby G., Minson A. C. 1989; The role of herpes simplex virus type 1 thymidine kinase in pathogenesis. J Gen Virol 70:869–879
    [Google Scholar]
  12. Erlich K. S., Mills J., Chatis P., Mertz G. J., Busch D. F., Follansbee S. E., Grant R. M., Crumpacker C. S. 1989; Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med 320:293–296
    [Google Scholar]
  13. Field H. J., Wildy P. 1978; The pathogenicity of thymidine kinase-deficient mutants of herpes simplex virus in mice. J Hyg 81:267–277
    [Google Scholar]
  14. Field H. J., Darby G. 1980; Pathogenicity in mice of strains of herpes simplex virus which are resistant to acyclovir in vitro and in vivo . Antimicrob Agents Chemother 17:209–216
    [Google Scholar]
  15. Grey F., Sowa M., Collins P., Fenton R. J., Harris W., Snowden W., Efstathiou S., Darby G. 2003; Characterization of a neurovirulent acyclovir-resistant variant of herpes simplex virus. J Gen Virol 84:1403–1410
    [Google Scholar]
  16. Hill T. J., Field H. J., Blyth W. A. 1975; Acute and recurrent infection with herpes simplex virus in the mouse: a model for studying latency and recurrent disease. J Gen Virol 28:341–353
    [Google Scholar]
  17. Hill E. L., Hunter G. A., Ellis M. N. 1991; In vitro and in vivo characterization of herpes simplex virus clinical isolates recovered from patients infected with human immunodeficiency virus. Antimicrob Agents Chemother 35:2322–2328
    [Google Scholar]
  18. Horsburgh B. C., Chen S. H., Hu A., Mulamba G. B., Burns W. H., Coen D. M. 1998; Recurrent acyclovir-resistant herpes simplex in an immunocompromised patient: can strain differences compensate for loss of thymidine kinase in pathogenesis?. J Infect Dis 178:618–625
    [Google Scholar]
  19. Hwang C. B., Horsburgh B. C., Pelosi E., Roberts S., Digard P., Coen D. M. 1994; A net +1 frameshift permits synthesis of thymidine kinase from a drug-resistant herpes simplex virus mutant. Proc Natl Acad Sci U S A 91:5461–5465
    [Google Scholar]
  20. Jacobson J. G., Ruffner K. L., Kosz-Vnenchak M., Hwang C. B., Wobbe K. K., Knipe D. M., Coen D. M. 1993; Herpes simplex virus thymidine kinase and specific stages of latency in murine trigeminal ganglia. J Virol 67:6903–6908
    [Google Scholar]
  21. Kit S., Kit M., Qavi H., Trkula D., Otsuka H. 1983; Nucleotide sequence of the herpes simplex virus type 2 (HSV-2) thymidine kinase gene and predicted amino acid sequence of thymidine kinase polypeptide and its comparison with the HSV-1 thymidine kinase gene. Biochim Biophys Acta 741:158–170
    [Google Scholar]
  22. Klemperer H. G., Haynes G. R., Shedden W. I., Watson D. H. 1967; A virus-specific thymidine kinase in BHK-21 cells infected with herpes simplex virus. Virology 31:120–128
    [Google Scholar]
  23. Kost R. G., Hill E. L., Tigges M., Straus S. E. 1993; Brief report: recurrent acyclovir-resistant genital herpes in an immunocompetent patient. N Engl J Med 329:1777–1782
    [Google Scholar]
  24. Larder B. A., Darby G. 1984; Virus drug-resistance: mechanisms and consequences. Antiviral Res 4:1–42
    [Google Scholar]
  25. Larder B. A., Darby G. 1985; Selection and characterisation of acyclovir-resistant herpes simplex virus type 1 mutants inducing altered DNA polymerase activities. Virology 146:262–271
    [Google Scholar]
  26. Lefkovits I., Waldemann H. 1979 Limiting Dilution Analysis of Cells in the Immune System Cambridge: Cambridge University Press;
    [Google Scholar]
  27. Nugier F., Colin J. N., Aymard M., Langlois M. 1992; Occurrence and characterization of acyclovir-resistant herpes simplex virus isolates: report on a two-year sensitivity screening survey. J Med Virol 36:1–12
    [Google Scholar]
  28. O'Brian J. J., Campoli-Richards D. M. 1989; Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs 37:233–309
    [Google Scholar]
  29. Parris D. S., Harrington J. E. 1982; Herpes simplex virus variants resistant to high concentrations of acyclovir exist in clinical isolates. Antimicrob Agents Chemother 22:71–77
    [Google Scholar]
  30. Sakuma S., Yamamoto M., Kumano Y., Mori R. 1988; An acyclovir-resistant strain of herpes simplex virus type 2 which is highly virulent for mice. Arch Virol 101:169–182
    [Google Scholar]
  31. Sasadeusz J. J., Sacks S. L. 1996; Spontaneous reactivation of thymidine kinase-deficient, acyclovir-resistant type-2 herpes simplex virus: masked heterogeneity or reversion?. J Infect Dis 174:476–482
    [Google Scholar]
  32. Sasadeusz J. J., Tufaro F., Safrin S., Schubert K., Hubinette M. M., Cheung P. K., Sacks S. L. 1997; Homopolymer mutational hot spots mediate herpes simplex virus resistance to acyclovir. J Virol 71:3872–3878
    [Google Scholar]
  33. Sibrack C. D., McLaren C., Barry D. W. 1982; Disease and latency characteristics of clinical herpes virus isolated after acyclovir therapy. Am J Med 73:372–375
    [Google Scholar]
  34. Tenser R. B., Dunstan M. E. 1979; Herpes simplex virus thymidine kinase expression in infection of the trigeminal ganglion. Virology 99:417–422
    [Google Scholar]
  35. Tenser R. B., Ressel S., Dunstan M. E. 1981; Herpes simplex virus thymidine kinase expression in trigeminal ganglion infection: correlation of enzyme activity with ganglion virus titer and evidence of in vivo complementation. Virology 112:328–341
    [Google Scholar]
  36. Wade J. C., Newton B., McLaren C., Flournoy N., Keeney R. E., Meyers J. D. 1983; Intravenous acyclovir to treat mucocutaneous herpes simplex virus infection after marrow transplantation: a double-blind trial. Ann Intern Med 96:265–269
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.18880-0
Loading
/content/journal/jgv/10.1099/vir.0.18880-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error