The Role of Herpes Simplex Virus Thymidine Kinase Expression in Pathogenesis and Latency

  • Richard B. Tenser
Part of the Frontiers of Virology book series (FRVIROLOGY, volume 3)


The role of herpes simplex virus (HSV) thymidine kinase (TK) expression for HSV neurovirulence and latency has been evaluated by many investigators. Although neurovirulence is complex and involves multiple host and viral factors, in studies with HSV TK-negative (TK) mutants, it seemed that TK expression was an important factor. This was apparent in experimental animal studies, as indicated by decreased replication of TK HSV mutants in neural tissue and by decreased mortality. Although some virulent TK HSV mutants have been reported, most investigators, including studies with HSV deletion mutants, have supported an important role for HSV TK expression and neurovirulence.

In early experimental animal studies in which HSV latency was defined by the ability to recover HSV from explants of latently infected ganglia, HSV TK expression also seemed important for latency. In more recent studies in which molecularly constructed TK HSV mutants were utilized, it was evident that ganglia could be infected with TK HSV so that HSV latency-associated transcript (LAT) was detected in ganglia during the period of latency. As in most previous studies, reactivation of TK HSV was not usually detected in ganglion explants. TK HSV could be rescued from such ganglia, however, by superinfection-complementation with TK+ HSV. These observations suggested that HSV TK expression was important for the reactivation of HSV from latent sensory ganglion neuron infection.

In recent, more speculative studies, the HSV tk gene and HSV TK mutants have been utilized therapeutically in experimental animal studies. In some of these studies, HSV TK expression was induced in neoplastic cells, which were then destroyed by TK-mediated antivirals. In other studies, TK HSV was used to destroy rapidly growing tumor cells or, alternatively, TK HSV was used to incorporate foreign genes into the nervous system.


Herpes Simplex Virus Type Thymidine Kinase Trigeminal Ganglion Thymidine Kinase Gene Thymidine Kinase Activity 
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  1. Allen GP, McGowan JJ, Gentry Ga, Randall CC (1978) Biochemical transformation of deoxythymidine kinase-deficient mouse cells with UV-irradiated equine herpesvirus type 1. J Virol 28: 361–367PubMedGoogle Scholar
  2. Al-Shawi R, Burke J, Wallace H, Jones C, Harrison S, Buxton D, Maley S, Chandley A, Bishop JO (1991) The herpes simplex virus type 1 thymidine kinase is expressed in the testes of transgenic mice under the control of a cryptic promoter. Mol Cell Biol 11: 4207–4216PubMedGoogle Scholar
  3. Bacchetti S, Graham FL (1977) Transfer of the gene for thymidine kinase to thymidine kinase-deficient human cells by purified herpes simplex viral DNA. Proc Natl Acad Sci USA 74: 1590–1594PubMedGoogle Scholar
  4. Birch CJ, Tyssen DP, Tachedjian G, Doherty R, Hayes K, Mijch A, Lucas CR (1992) Clinical effects and in vitro studies of trifluorothymidine combined with interferon-a for treatment of drug-resistant and -sensitive herpes simplex virus infections. J Infect Dis 166: 108–112PubMedGoogle Scholar
  5. Borrelli E, Heyman RA, Arias C, Sawchenko PE, Evans RM (1989) Transgenic mice with inducible dwarfism. Nature 339: 538–541PubMedGoogle Scholar
  6. Burns WH, Saral R, Santos GW, Laskin OL, Lietman PS, McLaren C, Barry DW (1982) Isolation and characterization of resistant herpes simplex virus after acyclovir therapy. Lancet 1: 421–423PubMedGoogle Scholar
  7. Chatis PA, Miller CH, Schrager LE, Crumpacker CS (1989) Successful treatment with foscarnet of an acyclovir-resistant mucocutaneous infection with herpes simplex virus in a patient with acquired immunodeficiency syndrome. N Engl J Med 320: 297–300PubMedGoogle Scholar
  8. Chen MS, Prusoff WH (1978) Association of thymidylate kinase activity with pyrimidine deoxyribonucleoside kinase induced by herpes simplex virus. J Biol Chem 253: 1325–1327PubMedGoogle Scholar
  9. Cheng Y-C (1977) A rational approach to the development of antiviral chemotherapy: alternative substrates of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) thymidine kinase (TK). Ann NY Acad Sci 284: 594–598PubMedGoogle Scholar
  10. Cheng Y-C, Ostrander M (1976) Deoxythymidine kinase induced in HeLa TK-cells by herpes simplex virus type I and type II. J Biol Chem 251: 2605–2610PubMedGoogle Scholar
  11. Cheng Y-C, Schinazi RF, Dutschman GE, Tan RS, Grill SP (1982) Virus-induced thymidine kinases as markers for typing herpes simplex viruses and for drug sensitivity assays. J Virol Methods 5: 209–217PubMedGoogle Scholar
  12. Chiocca EA, Choi BB, Cai W, DeLuca NA, Schaffer PA, DiFiglia M, Breakefield OX, Martuza RL (1990) Transfer and expression of the lac Z gene in rat brain neurons mediated by herpes simplex virus mutants. New Biol 2: 739–745PubMedGoogle Scholar
  13. Coen DM, Schaffer PA (1980) Two distinct loci confer resistance to acycloguanosine in herpes simplex virus type 1. Proc Natl Acad Sci USA 77: 2265–2269PubMedGoogle Scholar
  14. Coen DM, Fleming HE Jr, Leslie LK, Retondo MJ (1985) Sensitivity of arabinosyladenineresistant mutants of herpes simplex virus to other antiviral drugs and mapping of drug hypersensitivity mutations to the DNA polymerase locus. J Virol 53: 477–488PubMedGoogle Scholar
  15. Coen DM, Kosz-Vnenchak M, Jacobson JG, Leib DA, Bogard CL, Schaffer PA, Tyler KL, Knipe DM (1989a) Thymidine Kinase-Negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate. Proc Natl Acad Sci USA 86: 4736–4740PubMedGoogle Scholar
  16. Coen DM, Irmiere AF, Jacobson JG, Kerns KM (1989b) 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: 221–231PubMedGoogle Scholar
  17. Cooper GM (1973) Phosphorylation of 5-bromodeoxycytidine in cells infected with herpes simplex virus. Proc Natl Acad Sci USA 70: 3788–3792PubMedGoogle Scholar
  18. Cremer KJ, Bodemer M, Summers WP, Summers WC, Gesteland RF (1979) In vitro suppression of UAG and UGA mutants in the thymidine kinase gene of herpes simplex virus. Proc Natl Acad Sci USA 76: 430–434PubMedGoogle Scholar
  19. Crumpacker CS, Schnipper LE, Marlowe SI, Kowalsky PN, Hershey BJ, Levin MJ (1982) Resistance to antiviral drugs of herpes simplex virus isolated from a patient treated with acyclovir. N Engl J Med 306: 343–346PubMedGoogle Scholar
  20. Crumpacker CS, Kowalsky PN, Oliver SA, Schnipper LE, Field AK (1984) Resistance of herpes simplex virus to a 9-[2-hydroxy-1-(hydroxymethy) ethoxy]methyl guanine: physical mapping of drug synergism within the viral DNA polymerase locus. Proc Natl Acad Sci USA 81: 1556–1560PubMedGoogle Scholar
  21. Darby G, Field HJ, Salisbury SA (1981) Altered substrate specificity of herpes simplex virus thymidine kinase confers acyclovir-resistance. Nature 289: 81–83PubMedGoogle Scholar
  22. Darby G, Churcher MJ, Larder BA (1984) Cooperative effects between two acyclovir resistance loci in herpes simplex virus. J Virol 50: 838–846PubMedGoogle Scholar
  23. Darby G, Larder BA, Inglis MM (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: 753–758Google Scholar
  24. de Jong JT, Aker J, den Dulk H, van de Putte P, Giphart-Gassler M (1989) Cytosine methylation in the EcoR 1 site of active and inactive herpesvirus thymidine kinase promoters. Biochim Biophys Acta 1008: 62–70Google Scholar
  25. Derse D, Cheng Y-C, Furman PA,St. Clair MH, Elion GB (1981) Inhibition of purified human and herpes simplex virus-induced DNA polymerases by 9-(2-hydroxyethoxymethyl) guanine triphosphate. Effects on primer-template function. J Biol Chem 256: 11447–11451PubMedGoogle Scholar
  26. Dobersen MJ, Jerkofsky M, Greer S (1976) Enzymatic basis for the selective inhibition of varicella-zoster virus by 5-halogenated analogues of de oxycytidine. J Virol 20: 478–486PubMedGoogle Scholar
  27. Dubbs DR, Kit S (1964) Mutant strains of herpes simplex deficient in thymidine kinase-inducing activity. Virology 22: 493–502PubMedGoogle Scholar
  28. Dundarov S, Dundarova D, Todorov S, Kavaklova L, Falke D (1978) Induction capacity and influence of dThdMP on thymidine kinase activity of type 1 and 2 strains of herpes simplex virus. Arch Virol 56: 243–249PubMedGoogle Scholar
  29. Efstathiou S, Kemp S, Darby G, Minson AC (1989) The role of herpes simplex virus type 1 thymidine kinase in pathogenesis. J Gen Virol 70: 869–879PubMedGoogle Scholar
  30. Elion GB, Furman PA, Fyfe JA, deMiranda P, Beauchamp L, Schaeffer HJ (1977) Selectivity of action of an antiherpetic agent 9-(2-hydroxyethoxymethyl) guanine. Proc Natl Acad Sci USA 74: 5716–5720PubMedGoogle Scholar
  31. El Kareh A, Murphy AJM, Fichter T, Efstratiadis A (1985) “Transactivation” control signals in the promoter of the herpesvirus thymidine kinase gene. Proc Natl Acad Sci USA 82:1002–1006Google Scholar
  32. Ellis MN, Waters R, Hill EL, Lobe DC, Selleseth DW, Barry DW (1989) Orofacial infection of athymic mice with defined mixtures of acyclovir-susceptible and acyclovir-resistant herpes simplex virus type 1. Antimicrob Agents Chemother 33: 304–310PubMedGoogle Scholar
  33. Erlich KS, Mills J, Chatis P, Mertz GJ, Busch DF, Follansbee SE, Grant RM, Crumpacker CS (1989) Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med 320: 293–296PubMedGoogle Scholar
  34. Ezzeddine ZD, Martuza RL, Platika D, Short MP, Malick A, Choi B, Breakefield XO (1991) Selective killing of glioma cells in culture and in vivo by retrovirus transfer of the herpes simplex virus thymidine kinase gene. New Biol 3: 608–614PubMedGoogle Scholar
  35. Fang Z-Y, Tenser RB, Rapp F (1983) Hepatic infection by thymidine kinase-positive and thymidine kinase-negative herpes simplex virus after partial hepatectomy. Infect Immun 42: 402–408PubMedGoogle Scholar
  36. Field HJ, Darby G (1980) Pathogenicity in mice of strains of herpes simplex virus which are resistance to acyclovir and vitro and in vivo. Antimicrob Agents Chemother 17: 209–216PubMedGoogle Scholar
  37. Field HJ, Lay E (1984) Characterization of latent infections in mice inoculated with herpes simplex virus which is clinically resistant to acyclovir. Antiviral Res 4: 43–52PubMedGoogle Scholar
  38. Field HJ, Wildly P (1978) The pathogencity of thymidine kinase-dificient mutants of herpes simplex in mice. J Hyg 81: 267 277Google Scholar
  39. Friedmann T (1989) Progress toward human gene therapy. Science 244: 1275–1281PubMedGoogle Scholar
  40. Fyfe JA, Keller PM, Furman PA, Miller RL, Elion GB (1978) Thymidine kinase from herpes simplex virus phosphorylates the new antiviral compound 9-(2-hydroxyethoxymethyl) guanine. J Biol Chem 253: 8721–8727PubMedGoogle Scholar
  41. Fyfe JA, McKee SA, Keller PM (1983) Altered thymidine-thymidylate kinases from strains of herpes simplex virus with modified drug sensitivities to acyclovir and (E)-5-(2 bromovinyl)2’-deoxyuridine. Mol Pharmacod 24: 316–323Google Scholar
  42. Gordon YJ, Gilden DM, Becher Y (1983) HSV-1 thymidine kinase promotes virulence and latency in the mouse. Invest Ophthalmol Vis Sci 24: 599–602PubMedGoogle Scholar
  43. Gordon YJ, Rao H, Arullo-Cruz T (1984) Immunosuppression promotes ocular virus replication and CNS neurovirulence following corneal inoculation with an avirulent herpes simplex type 1 thymidine kinase negative mutant. Curr Eye Res 3: 651–657PubMedGoogle Scholar
  44. Graessmann A, Graessmann M (1988) DNA methylation, chromotin structure and regulation of herpes simplex virus tk gene expression. Gene 74: 135–137PubMedGoogle Scholar
  45. Griffin AM, Boursnell MEG (1990) Analysis of the nucleotide sequence of DNA from the region of the thymidine kinase gene of infectious laryngotracheitis virus: potential evolutionary relationships between the herpes virus subfamilies. J Gen Virol 71: 841–850PubMedGoogle Scholar
  46. Gronowitz JS, Kallander CFR (1980) Optimized assay for thymidine kinase and its applications to the detection of antibodies against herpes simplex virus type 1- and 2-induced thymidine kinase. Infect Immun 29: 425–434PubMedGoogle Scholar
  47. Gross MK, Merrill GF (1989) Thymidine kinase synthesis is repressed in nonreplicating muscle cells by a translational mechanism that does not affect the polysomal distribution of thymidine kinase mRNA. Proc Natl Acad Sci USA 86: 4987–4991PubMedGoogle Scholar
  48. Halliburton IW, Morse LS, Roizman B, Quinn KE (1980) Mapping of the thymidine kinase genes of type 1 and type 2 herpes simplex viruses using intertypic recombinants. J Gen Virol 49: 235–253PubMedGoogle Scholar
  49. Halliburton IW, Honess RW, Killington RA (1987) Virulence is not conserved in recombinants between herpes simplex virus types 1 and 2. J Gen Virol 68: 1435–1440PubMedGoogle Scholar
  50. Harrison PT, Thompson R, Davison AJ (1991) Evolution of herpesvirus thymidine kinase from cellular deoxycytidine kinase. J Gen Virol 72: 2583–2586PubMedGoogle Scholar
  51. Heyman RA, Borrelli E, Lesley J, Anderson D, Richman DD, Baird SM, Hyman R, Evans RM (1989) Thymidine kinase obliteration: creation of transgenic mice with controlled immune deficiency. Proc Natl Acad Sci USA 86: 2698 2702Google Scholar
  52. Hill EL, Hunter GA, Ellis MN (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: 2322–2328PubMedGoogle Scholar
  53. Ho DY (1992) Herpes simplex virus latency: molecular aspects. Prog Med Virol 39: 76–115PubMedGoogle Scholar
  54. Ho DY, Mocarski ES (1988) (3-Galactosidase as a marker in the peripheral and neural tissues of the herpes simplex virus-infected mouse. Virology 167: 279–283PubMedGoogle Scholar
  55. Honess RW, Watson DN (1974) Herpes simplex virus-specific polypeptides studies by polyacrylamide gel electrophoresis of immune precipitates. J Gen Virol 22: 171–185PubMedGoogle Scholar
  56. Honess RW, O’Hare PO, Young D (1982) Comparison of thymidine kinase activities induced in cells productively infected with herpesvirus saimiri and herpes simplex virus. J Gen Virol 58: 237–249PubMedGoogle Scholar
  57. Honess RW, Craxton MA, Williams L, Gompels UA (1989) A comparative analysis of the sequence of the thymidine kinase gene of a gammaherpesvirus, herpesvirus saimiri. J Gen Virol 70: 3003–3013PubMedGoogle Scholar
  58. Izant JG, Weintraub H (1984) Inhibition of thymidine kinase gene expression by anti-sense RNA: a molecular approach to genetic analysis. Cell 36: 1007–1015PubMedGoogle Scholar
  59. Izumi KM, Stevens JG (1988) Two thymidine kinase deficient herpes simplex viruses exhibit unexpected virulence properties. Microbiol Pathogen 4: 145–153Google Scholar
  60. Jacobson JG, Martin SL, Coen DM (1989) A conserved open reading frame that overlaps the herpes simplex virus thymidine kinase gene is important for viral growth in cells culture. J Virol 63: 1839–1843PubMedGoogle Scholar
  61. Jamieson AT, Subak-Sharpe JH (1978) Interallelic complementation of mutants of herpes simplex virus deficient in deoxypyrimidine kinase activity. Virology 85: 109–117PubMedGoogle Scholar
  62. Jamieson AT, Gentry GA, Subak-Sharpe JH (1974) Induction of both thymidine and deoxycytidine kinase activity by herpes virus. J Gen Virol 24: 465–480PubMedGoogle Scholar
  63. Kim SK, Wold BJ (1985) Stable reduction of thymidine kinase activity in cells expressing high levels of anti-sense RNA. Cell 42: 129–138PubMedGoogle Scholar
  64. Kit S (1985) Thymidine kinase. Microbiol Sci 2: 369–375PubMedGoogle Scholar
  65. Kit S, Dubbs DR (1963) Acquisition of thymidine kinase activity by herpes simplex infected mouse fibroblast cells. Biochem Biophys Res Commun 11: 55–59PubMedGoogle Scholar
  66. Kit S, Kit M, Pirtle EC (1985) Attenuated properties of thymidine kinase-negative deletion mutant of pseudorabies virus. Am J Vet Res 46: 1359–1367PubMedGoogle Scholar
  67. Kit S, Kit M, Ichimura H, Crandell R, McConnell S (1986) Induction of thymidine kinase activity by viruses with group B DNA genomes: bovine cytomegalovirus (bovine herpes-virus 4). Virus Res 4: 197–212PubMedGoogle Scholar
  68. Klein RJ (1982) Acyclovir-resistant herpes simplex virus. N Engl J Med 307: 681–682Google Scholar
  69. Klein RJ, DeStefano E, Brady E, Friedman-Kien AE (1980) Experimental skin infection with an acyclovir resistant herpes simplex virus mutant: response to antiviral treatment and protection against reinfection. Arch Virol 65: 237–246PubMedGoogle Scholar
  70. Klemperer HG, Haynes GR, Shedden WIH, Watson DH (1967) A virus-specific thymidine kinase in BHK21 cells infected with herpes simplex virus. Virology 31: 120–128PubMedGoogle Scholar
  71. Kosz-Vnenchak M, Coen DM, Knipe DM (1990) Restricted expression of herpes simplex virus lytic genes during establishment of latent infection by thymidine kinase-negative mutant viruses. J Virol 64: 5396–5402PubMedGoogle Scholar
  72. Larder BA, Darby G (1982) Properties of a novel thymidine kinase induced by an acyclovirresistant herpes simplex virus type 1 mutant. J Virol 42: 649–658PubMedGoogle Scholar
  73. Larder BA, Cheng Y-C, Darby G (1983) Characterization of abnormal thymidine kinases induced by drug-resistant strains of herpes simplex virus type 1. J Gen Virol 64: 523–532PubMedGoogle Scholar
  74. Lawson SN, Biscoe TJ (1979) Development of mouse dorsal root ganglia: an autoradiographic and quantitative study. J Neurocytol 8: 265–274PubMedGoogle Scholar
  75. Leib DA, Coen DM, Bogard CL, Hicks KA, Yager DR, Knipe DM, Tyler KL, Schaffer PA (1989a) Immediate-early regulatory gene mutants define different stages in the establishment and reactivation of herpes simplex virus latency. J Virol 63: 759–768PubMedGoogle Scholar
  76. Leib DA, Bogard CL, Kosz-Vnenchak M, Hicks KA, Coen DM, Knipe DM, Schaffer PA (1989b) A deletion mutant of the latency-associated transcript of herpes simplex virus type 1 reactivates from the latent state with reduced frequency. J Virol 63: 2893–2900PubMedGoogle Scholar
  77. Leib DA, Ruffner KL, Hildebrand C, Schaffer PA, Wright GE, Coen DM (1990) Specific inhibitors of herpes simplex virus thymidine kinase diminish reactivation of latent virus from explanted murine ganglia. Antimicrob Agents Chemother 34: 1285–1286PubMedGoogle Scholar
  78. Leist TP, Sandri-Goldin RM, Stevens JG (1989) Latent infections in spinal ganglia with thymidine kinase-deficient herpes simplex virus. J Virol 63: 4976–4978PubMedGoogle Scholar
  79. Lettler E, Arrand JR (1988) Characterization of the Epstein-Barr virus-encoded thymidine kinase expressed in heterologous eucaryotic and procaryotic systems. J Virol 62: 3892–3895Google Scholar
  80. Liu Q, Summers WC (1988) Site-directed mutagenesis of a nucleotide-binding domain in HSV-1 thymidine kinase: effects on catalytic activity. Virology 163: 638–642PubMedGoogle Scholar
  81. Mahalingham R, Cabirac G, Wellish M, Gilden D (1990) In-vitro synthesis of functional varicella zoster and herpes simplex viral thymidine kinase. Virus Genes 4: 105–120Google Scholar
  82. Maitland NJ, McDougall JK (1977) Biochemical transformation of mouse cells by fragments of herpes simplex virus DNA. Cell 11: 233–241PubMedGoogle Scholar
  83. Marcialis MA, LaColla P, Schivo ML, Flore O, Firinu A, Loddo B (1975) Low virulence and immunogenicity in mice and in rabbits of variants of herpes simplex virus resistant to 5-iodo2-deoxyuridine. Experientia 31: 502–503PubMedGoogle Scholar
  84. Martin JA, Duncan IB, Hall MJ, Wong-Kai-In P, Lambert RW, Thomas GJ (1989) New potent and selective inhibitors of herpes simplex virus thymidine kinase. Nucleosides nucleotides 8: 753–764Google Scholar
  85. Martin JL, Ellis MN, Keller PM, Biron KK, Lehrman SN, Barry DW, Furman PA (1985) Plaque autoradiography assay for the detection and quatitation of thymidine kinase-deficient and thymidine kinase altered mutants of herpes simplex virus in clinical isolates. Antimicrob Agents Chemother 28: 181–187PubMedGoogle Scholar
  86. Martin SL, Aparisio DI, Bandyopadhyay PK (1989) Genetic and biochemical characterization of the thymidine kinase gene from herpesvirus of turkeys. J Virol 63: 2847–2852PubMedGoogle Scholar
  87. Martuza RL, Malick A, Markert JM, Ruffner KL, Coen DM (1991) Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 252: 854–856PubMedGoogle Scholar
  88. May JT, Awad M, Reum A, Sheppard M (1990) Bovine herpes pammilitis virus thymidine kinase. Acta Virol 34: 188–192PubMedGoogle Scholar
  89. McDougall JK, Masse TH, Galloway DA (1980) Location and cloning of the herpes simplex virus type 2 thymidine kinase gene. J Virol 33: 1221–1224PubMedGoogle Scholar
  90. McGowan JJ, Allen GP, Barnett JM, Gentry GA (1980) Deoxythymidine kinase metabolism in equine herpesvirus type 3 infected horse embryo dermal fibroblasts. Virology 101: 516–519PubMedGoogle Scholar
  91. McKnight SL (1980) The nucleotide sequence and transcript map of the herpes simplex virus thymidine kinase gene. Nucleic Acids Res 8: 5949–5964PubMedGoogle Scholar
  92. McKnight SL, Gavis ER (1980) Expression of the herpes thymidine kinase gene in Xenopus laevis oocytes: an assay for the study of deletion mutants constructed in vitro. Nucleic Acids Res 8: 5931–5948PubMedGoogle Scholar
  93. Mengeling WL (1991) Virus reactivation in pigs latently infected with a thymidine kinase negative vaccine strain of pseudorabies virus. Arch Virol 120: 57–70PubMedGoogle Scholar
  94. Miller JM, Whetstone CA, Bello LJ, Lawrence WC (1991) Determination of ability of a thymidine kinase-negative deletion mutant of bovine herpesvirus-1 to cause abortion in cattle. Am J Vet Res 52: 1038–1043PubMedGoogle Scholar
  95. Miller RL, Iltis JP, Rapp F (1977) Differential effect of arabinofuranosylthymine on the replication of human herpesviruses. J Virol 23: 679–684PubMedGoogle Scholar
  96. Moolten FL, Wells JM (1990) Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. J Natl Cancer Inst 82: 297–300PubMedGoogle Scholar
  97. Munch-Peterson B, Tyrsted G (1988) Thymidine kinase in human leukemia. Expression of the lymphoblastic isoenzyme in three patients with acute myelocytic leukemia. Leuk Res 12: 173–178Google Scholar
  98. Munyon W, Kraiselburd E, Davis D, Mann J (1971) Transfer of thymidine kinase to thymidine kinaseless L cells by infection with ultraviolet-irradiated herpes simplex virus. J Virol 7: 813–820PubMedGoogle Scholar
  99. Nicolson L, Cullinane AA, Onions DE (1990) The nucleotide sequence of the equine herpesvirus 4 thymidine kinase gene. J Gen Virol 71: 1801–1805PubMedGoogle Scholar
  100. Nishiyama Y, Kimura H, Daikoku T (1991) Complementary lethal invasion of the central nervous system by nonneuroinvasive herpes simplex virus types 1 and 2. J Virol 65: 4520–4524PubMedGoogle Scholar
  101. Nohara H, Kaplan AS (1963) Induction of a new enzyme in rabbit kidney cells by pseudorabies virus. Biochem Biophys Res Commun 12: 189–193Google Scholar
  102. Nunberg JH, Wright DK, Cole GE, Petrovskis EA, Post LE, Compton T, Gilbert JH (1989) Identification of the thymidine kinase gene of feline herpesvirus: use of degenerate oligonucleotides in the polymerase chain reaction to isolate herpesvirus gene homologs. J Virol 63: 3240–3249PubMedGoogle Scholar
  103. Nutter LM, Grill SP, Dutschman GE, Sharma RA, Bobek M, Cheng Y-C (1987) Demonstration of viral thymidine kinase inhibitor and its effect on deoxynucleotide metabolism in cells infected with herpes simplex virus. Antimicrob Agents Chemother 31: 368–374PubMedGoogle Scholar
  104. Otsuka H, Kit S (1984) Nucleotide sequence of the marmoset herpesvirus thymidine kinase gene and predicted amino acid sequence of thymidine kinase polypeptide. Virology 135: 316–330PubMedGoogle Scholar
  105. Palella TD, Hidaka Y, Silverman LJ, Levine M, Glorioso J, Kelley WN (1989) Expression of human HPRT mRNA in brains of mice infected with a recombinant herpes simplex virus-1 vector. Gene 80: 137–144PubMedGoogle Scholar
  106. Parris DS, Harrington JE (1982) Herpes simplex virus variants resistant to high concentrations of acyclovir exist in clinical isolates. Antimicrob Agents Chemother 22: 71–77PubMedGoogle Scholar
  107. Pellicer A, Wigler M, Axel R, Silverstein S (1978) The transfer and stable integration of the HSV thymidine kinase gene into mouse cells. Cell 14: 133–141PubMedGoogle Scholar
  108. Post LE, Mackern S, Roizman B (1981) Regulation of a genes of herpes simplex virus: expression of chimeric genes produced by fusion of thymidine kinase with a gene promoters. Cell 24: 555–565PubMedGoogle Scholar
  109. Price RW, Khan A (1981) Resistance of peripheral autonomic neurons to in vivo productive infection by herpes simplex virus mutants deficient in thymidine kinase activity. Infect Immun 34: 571–580PubMedGoogle Scholar
  110. Prieto J, Martin Hernandez AM, Taborés E (1991) Loss of pseudorabies virus thymidine kinase activity due to a single base mutation and amino acid substitution. J Gen Virol 72: 1435–1439PubMedGoogle Scholar
  111. Reyes GR, Jeang K-T, Hayward GS (1982) Transfection with the isolated herpes simplex virus thymidine kinase genes. I. Minimal size of the active fragments from HSV-1 and HSV-2. J Gen Virol 62: 191–206PubMedGoogle Scholar
  112. Roberts GB, Fyfe JA, Gaillard RK, Short SA (1991) Mutant varicella-zoster virus thymidine kinase: correlation of clinical resistance and enzyme impairment. J Virol 65: 6407–6413PubMedGoogle Scholar
  113. Roubal J, Klein G (1981) Synthesis of thymidine kinase ( TK) in Epstein-Barr virus-superinfected Raji TK-negative cells. Intervirology 15: 43–48PubMedGoogle Scholar
  114. 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: 169–182PubMedGoogle Scholar
  115. Sanderson MR, Freemont PS, Murthy HMK, Krane JF, Summers WC, Steitz TA (1988) Purification and crystallization of thymidine kinase from herpes simplex virus type 1. J Mol Biol 202: 917–919PubMedGoogle Scholar
  116. Scott SD, Ross NLJ, Binns MM (1989) Nucleotide and predicted amino acid sequences of the Marek’s disease virus and turkey herpesvirus thymidine kinase genes; comparison with thymidine kinase genes of other herpesviruses. J Gen Virol 70: 3055–3065PubMedGoogle Scholar
  117. Sears AE, Meignier B, Roizman B (1985) Establishment of latency in mice by herpes simplex virus 1 recombinants that carry insertions affecting regulation of the thymidine kinase gene. J Virol 55: 410–416PubMedGoogle Scholar
  118. Shih M-F, Arsenakis M, Tiollais P, Roizman B (1984) Expression of hepatitis B virus S gene by herpes simplex virus type I vectors carrying a and 13 regulated gene chimeras. Proc Natl Acad Sci USA 81: 5867–5870PubMedGoogle Scholar
  119. Smiley JR (1980) Construction in vitro and rescue of a thymidine kinase-deficient deletion mutation of herpes simplex virus. Nature 285: 333–335PubMedGoogle Scholar
  120. Stanberry LR, Kit S, Myers MG (1985) Thymidine-kinase deficient herpes simplex virus type 2 genital infection in guinea pigs. J Virol 55: 322–328PubMedGoogle Scholar
  121. Steiner I, Spivack JG, Deshmane SL, Ace CI, Preston CM, Fraser NW (1990) A herpes simplex virus type 1 mutant containing a nontransinducing Vmw65 protein establishes latent infection in vivo in the absence of viral replication and reactivates efficiently from explanted trigeminal ganglia. J Virol 64: 1630–1638PubMedGoogle Scholar
  122. Stevens JG (1989) Human herpesviruses: a consideration of the latent state. Microbiol Rev 53: 318–332PubMedGoogle Scholar
  123. Stevens JG, Cook ML (1971) Latent herpes simplex virus in spinal ganglia of mice. Science 173: 843–845PubMedGoogle Scholar
  124. Stevens JG, Wagner EK, Devi-Rao GB, Cook ML, Feldman LT (1987) RNA complementary to a herpesvirus alpha gene mRNA is prominent in latently infected neurons. Science 235: 1056–1059PubMedGoogle Scholar
  125. Summers WC, Summers WP (1977) [125I]Deoxycytidine used in a rapid, sensitive, and specific assay for herpes simplex virus type 1 thymidine kinase. J Virol 24: 314–318PubMedGoogle Scholar
  126. Summers WP, Wagner M, Summers WC (1975) Possible peptide chain termination mutants in thymidine kinase gene of a mammalian virus, herpes simplex virus. Proc Natl Acad Sci USA 72: 4081–4084PubMedGoogle Scholar
  127. Swain MA, Galloway DA (1983) Nucleotide sequence of the herpes simplex virus type 2 thymidine kinase gene. J Viral 46: 1045–1050Google Scholar
  128. Tenser RB (1983) Intracerebral inoculation of newborn and adult mice with thymidine kinase-deficient mutants of herpes simplex virus type 1. J Infect Dis 147: 956PubMedGoogle Scholar
  129. Tenser R B, Dunstan ME (1979) Herpes simplex virus thymidine kinase expression in infection of the trigeminal ganglion. Virology 99: 417 422Google Scholar
  130. Tenser RB, Edris WA (1986) Thymidine kinase (TK) activity in herpes simplex virus type 1 recombinants that carry insertions affecting regulation of the TK gene. Virology 155: 257–261PubMedGoogle Scholar
  131. Tenser RB, Edris WA (1987) Trigeminal ganglion infection by thymidine kinase-negative mutants of herpes simplex virus after in vivo complementation. J Virol 61: 2171–2174PubMedGoogle Scholar
  132. Tenser RB, Miller RL, Rapp F (1979) Trigeminal ganglion infection by thymidine kinasenegative mutants of herpes simplex virus. Science 205: 915–917PubMedGoogle Scholar
  133. Tenser RB, Ressel S, Dunstan ME (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: 328–341PubMedGoogle Scholar
  134. Tenser RB, Dawson M, Ressel SJ, Dunstan ME (1982) Detection of herpes simplex virus mRNA in latently infected trigeminal ganglion neurons by in situ hybridization. Ann Neurol 11: 285–291PubMedGoogle Scholar
  135. Tenser RB, Ressel SJ, Fralish FA, Jones JC (1983) The role of pseudorabies virus thymidine kinase expression in trigeminal infection. J Gen Virol 64: 1369–1373PubMedGoogle Scholar
  136. Tenser RB, Jones JC, Ressel SJ (1985) Acute and latent infection by thymidine kinase mutants of herpes simplex virus type 2. J Infect Dis 151: 548–550PubMedGoogle Scholar
  137. Tenser RB, Hay KA, Edris WA (1989) Latency-associated transcript but not reactivatable virus is present in sensory ganglion neurons after inoculation of thymidine kinase-negative mutants of herpes simplex virus type 1. J Virol 63: 2861–2865PubMedGoogle Scholar
  138. Thouless ME, Skinner GRB (1971) Differences in the properties of thymidine kinase produced by cells infected with type 1 and type 2 herpes virus. J Gen Virol 12: 195–197PubMedGoogle Scholar
  139. van Oirschot JT, Terpstra C, Moorman RJM, Berns AJM, Gielkens All (1990) Safety of an Aujeszky’s disease vaccine based on deletion mutant strain 783 which does not express thymidine kinase and glycoprotein 1. Vet Rec 127: 443–446PubMedGoogle Scholar
  140. Veerisetty V, Gentry GA (1983) Alterations in substrate specificity and physiochemical properties of deoxythymidine kinase of a drug-resistant herpes simplex virus type 1 mutant. J Virol 46: 901–908PubMedGoogle Scholar
  141. Veerisetty V, Veerisetty IK, Gentry GA (1983) Alterations in the recognition of nucleoside analogues as substrates by the deoxythymidine kinase of a 5-methoxymethyldeoxyuridineresistant mutant of herpes simplex virus type 1 mutant. J Gen Virol 64: 2767–2770PubMedGoogle Scholar
  142. Volz DM, Lager LM, Mengeling WL (1992) Latency of a thymidine kinase-negative pseudorabies vaccine virus detected by the polymerase chain reaction. Arch Virol 122: 341–348PubMedGoogle Scholar
  143. Wagner MJ, Sharp JA, Summers WC (1981) Nucleotide sequence of the thymidine kinase gene of herpes simplex virus type 1. Proc Natl Acad Sci USA 78: 1441–1445PubMedGoogle Scholar
  144. Weinmaster GA, Misra V, McGuire R, Babiuk LA, DeClercq E (1982) Bovid herpesvirus type-1 ( Infectious bovine rhinotracheitis virus)-induced thymidine kinase. Virology 118: 191–201PubMedGoogle Scholar
  145. Westheim AI, Tenser RB, Marks JG (1987) Acyclovir resistance in a patient with chronic mucocutaneous herpes simplex infection. J Am Acad Dermatol 17: 875–880PubMedGoogle Scholar
  146. Whetstone CA, Miller JM, Seal BS, Bello LJ, Lawrence WC (1992) Latency and reactivation of a thymidine kinase-negative bovine herpesvirus l deletion mutant. Arch Viro 122: 207–214Google Scholar
  147. Whitby AJ, Blyth WA, Hill TJ (1987) The effect of DNA hypomethylating agents on the reactivation of herpes simplex virus from latently infected mouse ganglia in vitro. Arch Virol 97: 137–144PubMedGoogle Scholar
  148. Wigler M, Silverstein S, Lee L-S, Pellicer A, Cheng Y-C, Axel R (1977) Transfer of purified herpes virus thymidine kinase gene to cultured mouse cells. Cell 11: 223–232PubMedGoogle Scholar
  149. Wilcox CL, Crnic LS, Pizer LI (1992) Replication, latent infection, and reactivation in neuronal culture with a herpes simplex virus thymidine kinase-negative mutant. Virology 187: 348–352PubMedGoogle Scholar
  150. Yamada N, Sawaski Y, Nakajima (1980) Thymidine kinase isozymes in rat cerebellum. Correlation of the activities of specific isozymes with DNA synthesis. Brain Res 195: 485–488Google Scholar
  151. Yusa T, Yamaguchi Y, Ohwada H, Hayashi Y, Kuroiwa N, Morita T, Asanagi M, Moriyama Y, Fujimura S (1988) Activity of the cytosolic isozyme of thymidine kinase in human primary lung tumors with reference to malignancy. Cancer Res 48: 5001–5006PubMedGoogle Scholar
  152. Zimmerman N, Beck-Sickinger AG, Folkens G, Krickl S, Müller I (1991) Conformational and epitope mapping of herpes simplex virus type 1 thymidine kinase using synthetic peptide segments. Eur J Biochem 200: 519–528Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1994

Authors and Affiliations

  • Richard B. Tenser
    • 1
  1. 1.Department of Medicine (Neurology) and Microbiology and ImmunologyPennsylvania State University College of MedicineHersheyUSA

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