1887

Abstract

We have mutagenized and mapped the gene encoding the large subunit of ribonucleotide reductase (RR) in pseudorabies virus (PRV; synonyms Aujeszky's disease virus, suid herpesvirus type 1). PRV strains carrying an oligonucleotide that leads to termination of translation of the RR gene are avirulent for mice. We subsequently constructed a PRV strain carrying a deletion in the RR gene and also a PRV strain carrying both the deletion in the RR gene and a deletion in the glycoprotein g1 gene, which is a marker for PRV virulence. Both PRV strains were assayed for virulence and immunogenicity in pigs, the natural host for PRV. In contrast to a marker-rescued PRV strain, these RR-deleted mutants were avirulent, were shed in very low titres in the oropharyngeal fluid by the animals, and induced low titres of neutralizing antibodies. However, protection against clinical signs after infection with virulent PRV was induced by both RR-deleted mutants. The relative importance of viral RR and thymidine kinase enzymes for deoxynucleotide synthesis in viral replication is discussed. In addition, we discuss the potential use of RR as a target for anti-herpesviral drugs and the use of PRV strains, deleted for the RR gene, as vaccine strains.

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1993-03-01
2024-04-20
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References

  1. Au M. A., Prakash S. S., Jarjwalla R. J. 1992; Localization of the antigenic sites and intrinsic protein kinase domain within a 300 amino acid segment of the ribonucleotide reductase large subunit from herpes simplex virus type 2. Virology 187:360–367
    [Google Scholar]
  2. 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 HindIII fragment K region of the herpes simplex virus type 1 genome. Journal of Virology 37:1011–1027
    [Google Scholar]
  3. Averett D. R., Lubbers C., Elion G. B., Spector T. 1983; Ribonucleotide reductase induced by herpes simplex type 1 virus. Characterization of a distinct enzyme. Journal of Biological Chemistry 258:9831–9838
    [Google Scholar]
  4. 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]
  5. Bacchetti S., Evelegh M. J., Muirhead B. 1986; Identification and separation of the two subunits of herpes simplex virus ribonucleotide reductase. Journal of Virology 57:1177–1181
    [Google Scholar]
  6. Baskerville A., McFerran J. B., Dow C. 1973; Aujeszky’s disease in pigs. Veterinary Bulletin 43:465–480
    [Google Scholar]
  7. Ben-Porat T., Kaplan A. S. 1985 Molecular biology of pseudorabies virus. In The Herpesviruses vol 3 pp. 105–173 Edited by Roizman B. New York & London: Plenum Press;
    [Google Scholar]
  8. Ben-Porat T., Veach R. A., Ihara S. 1983; Localization of the regions of homology between the genomes of herpes simplex virus type 1, and pseudorabies virus. Virology 127:194–204
    [Google Scholar]
  9. Brandt C. R., Kintner R. L., Pumfery A. M., Visalli R. J., Grau D. R. 1991; The herpes simplex virus ribonucleotide reductase is required for ocular virulence. Journal of General Virology 72:2043–2049
    [Google Scholar]
  10. 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]
  11. Card J. P., Whealy M. E., Robbins A. K., Enquist L. W. 1992; Pseudorabies virus envelope glycoprotein gl influences both neurotropism and virulence during infection of the rat visual system. Journal of Virology 66:3032–3041
    [Google Scholar]
  12. Chee M. S., Bankier A. T., Beck S., Bohni R., Brown C. M., Cerny R., Horsnell T., Hutchinson C. A., , III, Kouzarides T., Martignetti J. A., Preddie E., Satchwell S. C., Tomlinson P., Weston K. M., Barrell B. G. 1990; Analysis of the proteincoding content of the sequence of human cytomegalovirus strain AD169. Current Topics in Microbiology and Immunology 154:125–169
    [Google Scholar]
  13. Chung T. D., Wymer J. P., Smith C. C, Kulka M., Aurelian L. 1989; Protein kinase activity associated with the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10). Journal of Virology 63:3389–3398
    [Google Scholar]
  14. Chung T. D., Wymer J. P., Kulka M., Smith C. C., Aurelian L. 1990; Myristylation and polylysine-mediated activation of the protein kinase domain of the large subunit of herpes simplex virus type 2 ribonucleotide reductase. Virology 179:168–178
    [Google Scholar]
  15. Cohen E. A., Brazeau P., Gaudreau P., Langelier Y. 1986; Specific inhibition of herpesvirus ribonucleotide reductase by a nonapeptide derived from the carboxyterminus of subunit 2. Nature, London 321:441–443
    [Google Scholar]
  16. Cohen E. A., Paradis H., Gaudreau P., Brazeau P., Langelier Y. 1987; Identification of viral polypeptides involved in pseudorabies virus ribonucleotide reductase activity. Journal of Virology 61:2046–2049
    [Google Scholar]
  17. Daikoku T., Yamamoto N., Maeno K., Nishiyama Y. 1991; Role of viral ribonucleotide reductase in the increase of dTTP pool size in herpes simplex virus-infected Vero cells. Journal of General Virology 72:1441–1444
    [Google Scholar]
  18. Davison A. J., Scott J. E. 1986; The complete DNA sequence of varicella-zoster virus. Journal of General Virology 67:1759–1816
    [Google Scholar]
  19. Davison A. J., Wilkie N. M. 1983; Localization and orientation of homologous sequences in the genomes of five herpesviruses. Journal of General Virology 64:1927–1942
    [Google Scholar]
  20. de Wind N., Zijderveld A., Glazenburg K., Berns A. 1990; Linker insertion mutagenesis of herpesviruses : inactivation of single genes within the Us region of pseudorabies virus. Journal of Virology 64:4691–4696
    [Google Scholar]
  21. de Wind N., Domen J., Berns A. 1992; Herpesviruses encode an unusual protein-serine/threonine kinase which is nonessential for growth in cultured cells. Journal of Virology 66:5200–5209
    [Google Scholar]
  22. Draper K. G., Fink R. J., Wagner E. K. 1982; Detailed characterization of an apparently unspliced /? herpes simplex virus type 1 gene mapping in the interior of another. Journal of Virology 43:1123–1128
    [Google Scholar]
  23. 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]
  24. Dutia B. M., Frame M. C., Subak-Sharpe M. C., Clark W. N., Marsden H. S. 1986; Specific inhibition of herpes ribonucleotide reductase by synthetic peptides. Nature, London 321:439–441
    [Google Scholar]
  25. 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 85:1581–1587
    [Google Scholar]
  26. Galloway D. A., Swain M. A. 1984; Organization of the left-hand end of the herpes simplex type 2 BglII N fragment. Journal of Virology 49:724–730
    [Google Scholar]
  27. Galloway D. A., Goldstein L. C., Lewis J. B. 1982; Identification of proteins encoded by a fragment of herpes simplex virus type 2 DNA that has transforming activity. Journal of Virology 42:530–532
    [Google Scholar]
  28. Gibson T., Stockwell P., Ginsburg M., Barrell B. 1984; Homology between two EBV early genes and HSV ribonucleotide reductase and 38K genes. Nucleic Acids Research 12:5087–5099
    [Google Scholar]
  29. Goldstein D. J., Weller S. K. 1988a; Herpes simplex virus type l-induced ribonucleotide reductase activity is dispensable for virus growth and DNA synthesis: isolation and characterization of an ICP6 lacZ insertion mutant. Journal of Virology 62:196–205
    [Google Scholar]
  30. Goldstein D. J., Weller S. K. 1988b; Factor(s) present in herpes simplex 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]
  31. Ingemarson R., Lankinen H. 1987; The herpes simplex virus type 1 ribonucleotide reductase is a tight complex of the type α2β2 composed of 40K and 140K proteins, of which the latter shows multiple forms due to proteolysis. Virology 156:417–422
    [Google Scholar]
  32. Jacobson J. G., Leib D. A., Goldstein D. J., Bogard C. L., Schaffer P. A., Weller S. K., Coen 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]
  33. Jamieson A. T., Gentry G. A., Subak-Sharpe J. H. 1974; Induction of both thymidine and deoxycytidine kinase activity by herpes viruses. Journal of General Virology 24:465–180
    [Google Scholar]
  34. Kimman T., de Wind N., Oei-Lie N., Pol J. M. A., Berns A. J. M., Gielkens A. L. J. 1992; Contribution of single genes within the unique short region of Aujeszky’s disease virus (suid herpesvirus type 1) to virulence, pathogenesis and immunogenicity. Journal of General Virology 73:243–251
    [Google Scholar]
  35. Lankinen H., Graslund 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]
  36. McClements W., Yamanaka G., Garsky V., Perry H., Bacchetti S., Colonno R., Stein R. B. 1988; Oligopeptides inhibit the ribonucleotide reductase of herpes simplex virus by causing subunit separation. Virology 162:270–273
    [Google Scholar]
  37. 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 sequence of the long unique region in the genome of herpes simplex virus type 1. Journal of General Virology 69:1531–1574
    [Google Scholar]
  38. McGregor S., Easterday B. C., Kaplan A. S., Ben-Porat T. 1985; Vaccination of swine with thymidine kinase-deficient mutants of pseudorabies virus. American Journal of Veterinary Research 46:1494–1497
    [Google Scholar]
  39. McLauchlan J., Clements J. B. 1982; A 3′ co-terminus of two early herpes simplex virus type 1 mRNAs. Nucleic Acids Research 10:501–512
    [Google Scholar]
  40. McLauchlan J., Clements J. B. 1983a; DNA sequence homology between two co-linear loci on the HSV genome which have different transforming abilities. EMBO Journal 2:1953–1961
    [Google Scholar]
  41. McLauchlan J., Clements J. B. 1983b; 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]
  42. Marchioli C. C., Yancey R. J. Jr, Wardley R. C, Thomsen D. R., Post L. E. 1987; A vaccine strain of pseudorabies virus with deletions in the thymidine kinase and glycoprotein X genes. American Journal of Veterinary Research 48:1577–1583
    [Google Scholar]
  43. Mettenleiter T. S., Zsak L., Kaplan A. S., Ben-Porat T., Lomniczi B. 1987; Role of a structural glycoprotein of pseudorabies in virus virulence. Journal of Virology 61:4030–4032
    [Google Scholar]
  44. Moormann R. J. M., de Rover T., Briaire J., Peeters B. P. H., Gielkens A. L. J., van Oirschot J. T. 1990; Inactivation of the thymidine kinase gene of a gl deletion mutant of pseudorabies virus generates a safe but still highly immunogenic vaccine strain. Journal of General Virology 71:1591–1595
    [Google Scholar]
  45. Nikas I., McLauchlan J., Davison A. J., Taylor W. R., Clements J. B. 1986; Structural features of ribonucleotide reductase. Proteins 1:376–384
    [Google Scholar]
  46. Nutter L. M., Grill S. P., Cheng Y. 1985; The sources of thymidine nucleotides for viral DNA synthesis in herpes simplex virus type 2-infected cells. Journal of Biological Chemistry 260:13272–13275
    [Google Scholar]
  47. Petrovskis E. A., Timmins J. G., Post L. E. 1986; Use of /.gtl 1 to isolate genes for two pseudorabies virus glycoproteins with homology to herpes simplex and varicella-zoster virus glycoproteins. Journal of Virology 60:185–193
    [Google Scholar]
  48. Preston V. G., Darling A. J., McDougall I. M. 1988; The herpes simplex virus type 1 temperature-sensitive mutant tsl222 has a single base pair deletion in the small subunit of ribonucleotide reductase. Virology 167:458–167
    [Google Scholar]
  49. Quint W., Gielkens A., van Oirschot J., Berns A., Cuypers H. T. 1987; Construction and characterization of deletion mutants of pseudorabies virus: a new generation of ‘live’ vaccines. Journal of General Virology 68:523–534
    [Google Scholar]
  50. Reichard P. 1988; Interactions between deoxyribonucleotide and DNA synthesis. Annual Review of Biochemistry 57:349–374
    [Google Scholar]
  51. Robbins A. K., Watson R. J., Whealy M. E., Hays W. W., Enquist L. W. 1986; Characterization of a pseudorabies virus glycoprotein gene with homology to herpes simplex virus type 1 and type 2 glycoprotein C. Journal of Virology 58:339–347
    [Google Scholar]
  52. Sambrook J., Fritsch E. F., Maniates T. 1989 Molecular Cloning: A Laboratory Manual, 2nd edn. New York: Cold Spring Harbor Laboratory;
    [Google Scholar]
  53. Sanger F., Nicklen S., Coulson A. R. 1977; DNA sequencing with chain-terminating inhibitors. Proceedings of the National Academy of Sciences, U.S.A. 74:5463–5467
    [Google Scholar]
  54. Shipman L. Jr, Smith S. H., Drach J. C., Klayman D. L. 1986; Thiosemicarbazones of 2-acetylpyridine, 2-acetylquinoline, 1-acetyl-isoquinoline and related compounds as inhibitors of herpes simplex virus in vitro and in a cutaneous herpes guinea pig model. Antiviral Research 6:197–222
    [Google Scholar]
  55. Spector T., Averett D. R., Nelson D. J., Lambe C. U., Morrison R. W., , Jr, St Clair M. H., Furman P. A. 1985; Potentiation of antiherpetic activity of acyclovir by ribonucleotide reductase inhibition. Proceedings of the National Academy of Sciences, U.S.A. 82:4354–4357
    [Google Scholar]
  56. Swain M. A., Galloway D. 1986; Herpes simplex virus specifies two subunits of ribonucleotide reductase encoded by 3′-coterminal transcripts. Journal of Virology 57:802–808
    [Google Scholar]
  57. Turk S. R., Shipman C. Jr, Drach J. C. 1986a; Structure activity relationships among a-(7V)-heterocyclic acyl thiosemicarbazones and related compounds as inhibitors of herpes simplex virus type 1-specified ribonucleoside diphosphate reductase. Journal of General Virology 67:1625–1632
    [Google Scholar]
  58. Turk S. R., Shipman C. Jr, Drach J. C. 1986b; Selective inhibition of herpes simplex virus ribonucleoside diphosphate reductase by derivatives of 2-acetylpyridine thiosemicarbazone. Biochemical Pharmacology 35:1539–1545
    [Google Scholar]
  59. Turk S. R., Kik N. A., Birch G. M., Chiego D. J. Jr, Shipman L. Jr. 1989; Herpes simplex virus type 1 ribonucleotide reductase null mutants induce lesions in guinea pigs. Virology 173:733–735
    [Google Scholar]
  60. Van Oirschot J. T., Rziha H. J., Moonen P. J. L. M., Pol J. M. A., van Zaane D. 1986; Differentiation of serum antibodies from pigs vaccinated or infected with Aujeszky’s disease virus by a competitive enzyme immunoassay. Journal of General Virology 67:1179–1182
    [Google Scholar]
  61. van Oirschot J. T., Terpstra C., Moormann R. J. M., Berns A. J. M., Gielkens A. L. J. 1990; Safety of an Aujeszky’s disease vaccine based on deletion mutant strain 783 which does not express thymidine kinase and glycoprotein I. Veterinary Record 127:430–446
    [Google Scholar]
  62. van Oirschot J. T., Moormann R. J. M., Berns A. J. M., Gielkens A. L. J. 1991; Efficacy of a pseudorabies virus vaccine based on deletion mutant strain 783 that does not express thymidine kinase and glycoprotein I. American Journal of Veterinary Research 52:1056–1060
    [Google Scholar]
  63. van Zijl M., Quint W., Briaire J., De Rover T., Gielkens A., Berns A. 1988; Regeneration of herpesviruses from molecularly cloned subgenomic fragments. Journal of Virology 62:2191–2195
    [Google Scholar]
  64. Wathen M. W., Wathen L. M. K. 1986; Characterization and mapping of a nonessential pseudorabies virus glycoprotein. Journal of Virology 58:173–178
    [Google Scholar]
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