1887

Abstract

We used a herpes simplex virus (HSV) type 1 ribonucleotide reductase (RR) null mutant (ICP6Δ) to study the role of HSV-1 RR in ocular HSV infections. We found that ICP6Δ was unable to induce vascularization of the cornea or stromal keratitis following inoculation into the cornea of BALB/c mice, but was able to induce a transient mild blepharitis. The parental strain (HSV-1 KOS) and a revertant of ICP6Δ, ICP6Δ 3.1, both caused severe ocular disease, indicating that HSV-1 RR is required for ocular virulence in mice. ICP6Δ grew poorly (Vero and BALB/c 3T3 fibroblasts) and (eye, trigeminal ganglia and brain) compared to ICP6Δ3.1 and HSV-1 KOS, suggesting that the avirulence of ICP6Δ is due to poor growth in the host. ICP6Δ also grew less well in primary human corneal fibroblasts, suggesting that RR may be required for virulence in humans. These results indicate that drugs inhibiting the function of RR might be effective in treating ocular HSV infections.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-72-9-2043
1991-09-01
2022-08-18
Loading full text...

Full text loading...

/deliver/fulltext/jgv/72/9/JV0720092043.html?itemId=/content/journal/jgv/10.1099/0022-1317-72-9-2043&mimeType=html&fmt=ahah

References

  1. Anderson K. P., Frink R. J., Devi G. B., Gaylord B. H., Costa R. H., Wagner E. K. 1981; Detailed characterization of the mRNA mapping in the Hin dIII fragment K region of the herpes simplex virus type 1 genome. Journal of Virology 37:1011–1027
    [Google Scholar]
  2. Bacchetti S., Evelegh M. J., Muirhead B., Sartori C. S., Huszar D. 1984; Immunological characterization of herpes simplex virus type 1 and 2 polypeptide(s) involved in viral ribonucleotide reductase activity. Journal of Virology 49:591–593
    [Google Scholar]
  3. Brandt C. R., Grau D. R. 1990; Mixed infection with HSV-1 generates recombinants with increased ocular and neurovirulence. Investigative Ophthalmology and Visual Science 31:2214–2223
    [Google Scholar]
  4. Cameron J. M., McDougall I., Marsden H. S., Preston V. G., Ryan D. M., Subak-Sharpe J. H. 1988; Ribonucleotide reductase encoded by herpes simplex virus is a determinant of the pathogenicity of the virus in mice and a valid antiviral target. Journal of General Virology 69:2607–2612
    [Google Scholar]
  5. Caras I. W., Levenson B. B., Fabry M., Williams S. R., Martin D. W. Jr 1985; Cloned mouse ribonucleotide reductase subunit Ml cDNA reveals amino acid sequence homology with Escherichia coli and herpes virus ribonucleotide reductases. Journal of Biological Chemistry 260:7015–7022
    [Google Scholar]
  6. Carlson J., Fuchs J. A., Messing J. 1984; Primary structure of the Escherichia coli ribonucleoside diphosphate reductase. Proceedings of the National Academy of Sciences, U.S.A 81:4294–4297
    [Google Scholar]
  7. Child S. J., Palumbo G. J., Buller R. M. L., Hruby D. E. 1990; Insertional inactivation of the large subunit of ribonucleotide reductase encoded by vaccinia virus is associated with reduced virulence in vivo. Virology 174:625–629
    [Google Scholar]
  8. Cohen E. A., Gadreau P., Brazeau P., Langelier Y. 1986; Specific inhibition of herpes virus ribonucleotide reductase by a nonapeptide derived from the carboxy terminus of subunit 2. Nature, London 321:441–443
    [Google Scholar]
  9. Cohen J. C., Henry B. E., Randall C. C. Callaghan D. 1977; Ribonucleotide reductase activity in hydroxyurea resistant herpes virus replication. Proceedings of the Society for Experimental Biology and Medicine 155:395–399
    [Google Scholar]
  10. Dutia B. M. 1983; Ribonucleotide reductase induced by herpes simplex virus has a virus-specified constituent. Journal of General Virology 64:513–521
    [Google Scholar]
  11. Dutia B. M., Frame M. C., Subak-Sharpe J. H., Clark W. N., Marsden H. S. 1986; Specific inhibition of herpes virus ribonucleotide reductase by synthetic peptides. Nature, London 321:439–441
    [Google Scholar]
  12. Frame M. C., Marsden H. S., Dutia B. M. 1985; The ribonucleotide reductase induced by herpes simplex virus type 1 involves minimally a complex of two polypeptides (136K and 38K). Journal of General Virology 66:1581–1587
    [Google Scholar]
  13. Frenkel E. D., Skinner W. N., Smiley J. D. 1964; Studies on a metabolic defect induced by hydroxyurea (NSC-32065). Cancer Chemotherapy Reports 40:19–22
    [Google Scholar]
  14. Goldstein D. J., Weller S. K. 1988; Factor(s) present in herpes simplex virus type 1-infected cells can compensate for the loss of the large subunit of the viral ribonucleotide reductase: characterization of an ICP6 deletion mutant. Virology 166:41–51
    [Google Scholar]
  15. Grau D. R., Visalli R. J., Brandt C. R. 1989; Herpes simplex virus stromal keratitis is not titer-dependent and does not correlate with neurovirulence. Investigative Ophthalmology and Visual Science 30:2474–2480
    [Google Scholar]
  16. Henry B. E., Glaser R., Hewetson J., O’Callaghan D. J. 1978; Expression of altered ribonucleotide reductase activity associated with the replication of the Epstein-Barr virus. Virology 89:262–271
    [Google Scholar]
  17. Honess R. W., Roizman B. 1973; Proteins specified by herpes simplex virus. XI. Identification and relative molar rates of synthesis of structural and non-structural herpes virus polypeptides in infected cells. Journal of Virology 12:1346–1365
    [Google Scholar]
  18. Honess R. W., Roizman B. 1974; Regulation of herpes virus macromolecular synthesis. I. Cascade regulation of the synthesis of three groups of viral proteins. Journal of Virology 14:8–19
    [Google Scholar]
  19. Huszar D., Bacchetti S. 1981; Partial purification and characterization of ribonucleotide reductase induced by HSV infection of mammalian cells. Journal of Virology 37:580–588
    [Google Scholar]
  20. Jacobson J. G., Leib D. A., Goldstein D. J., Bogard C. L., Schaffer P. A., Weller S. K., Cohen D. M. 1989; A herpes simplex virus ribonucleotide reductase deletion mutant is defective for productive acute and reactivatable latent infections of mice and for replication in mouse cells. Virology 173:276–283
    [Google Scholar]
  21. Katz J. P., Bodin E. T., Loen D. M. 1990; Quantitative polymerase chain reaction analysis of herpes simplex virus DNA in ganglia of mice infected with replication-incompetent mutants. Journal of Virology 64:4288–4295
    [Google Scholar]
  22. Lankinen H., Gräslund A., Thelander L. 1982; Induction of a new ribonucleotide reductase after infection of mouse L cells with pseudorabies virus. Journal of Virology 41:893–900
    [Google Scholar]
  23. McGeoch D. J., Dalrymple M. A., Davison A. J., Dolan A., Frame M. C., McNab D., Perry L. J., Scott J. E., Taylor P. 1988; The complete DNA sequences of the long unique region in the genome of herpes simplex virus type 1. Journal of General Virology 69:1531–1574
    [Google Scholar]
  24. McLauchlan J., Clements J. B. 1983; Organization of the herpes simplex virus type 1 transcription unit encoding two early proteins with molecular weights of 140000 and 40000. Journal of General Virology 64:997–1006
    [Google Scholar]
  25. Ponce de Leon M., Eisenberg R. J., Cohen G. H. 1977; Ribonucleotide reductase from herpes simplex virus (types 1 and 2) infected and uninfected KB cells: properties of the partially purified enzymes. Journal of General Virology 36:163–173
    [Google Scholar]
  26. Preston V. G., Palfreyman J. W., Dutia B. M. 1984; Identification of a herpes simplex virus type 1 polypeptide which is a component of the virus-induced ribonucleotide reductase. Journal of General Virology 65:1457–1466
    [Google Scholar]
  27. Preston V. G., Darling A. J., McDougall I. M. 1988; The herpes simplex virus type 1 temperature-sensitive mutant ts 1222 has a single base pair deletion in the small subunit of ribonucleotide reductase. Virology 167:458–467
    [Google Scholar]
  28. Spector T. 1985; Inhibition of ribonucleotide reductases encoded by herpes simplex viruses. Pharmacology and Therapeutics 31:295–302
    [Google Scholar]
  29. Swain M. A., Galloway D. A. 1986; Herpes simplex virus specifies two subunits of ribonucleotide reductase encoded by 3′ coterminal transcripts. Journal of Virology 57:802–808
    [Google Scholar]
  30. Thelander L., Reichard P. 1979; Reduction of ribonucleotides. Annual Review of Biochemistry 48:133–158
    [Google Scholar]
  31. Turk S. R., Kik N. A., Birch G. M., Chiego D. J. Jr, Shipman J. C. 1989; Herpes simplex virus type 1 ribonucleotide reductase null mutants induce lesions in guinea pigs. Virology 173:733–735
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-72-9-2043
Loading
/content/journal/jgv/10.1099/0022-1317-72-9-2043
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

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