1887

Abstract

During neuronal latency of herpes simplex virus (HSV)-1, the latency-associated transcript (LAT) is the only viral gene readily detectable. LAT is required for the high-level reactivation phenotype in animal models. LAT's anti-apoptotic activity was recently demonstrated by our group and it was proposed that LAT's anti-apoptotic function is involved in enhancing the reactivation phenotype. Recently, using chimeric virus CJLAT, it was shown that the reactivation phenotype of LAT mutant dLAT2903 can be restored to wild-type levels by inserting the bovine herpes virus (BHV)-1 latency-related (LR) gene into the LAT locus of this HSV-1 LAT deletion mutant. Although transcription of the LR gene, like LAT, inhibits apoptosis, LR appears to be multifunctional. To investigate whether the LR gene's anti-apoptotic function was responsible for restoring the high-reactivation phenotype, a mutated BHV-1 LR gene was inserted into the LAT locus of HSV-1 generating the chimeric virus CJLATmut. This mutation consists of three stop codons inserted just after the ATG of the first LR open reading frame (ORF2). In plasmids and in a BHV-1 mutant, this mutation eliminated the LR gene's anti-apoptotic activity, strongly suggesting that ORF2 encodes a protein responsible for LR's anti-apoptotic activity. Reactivation of the CJLATmut virus, in both rabbits and mice, was significantly lower than in wild-type McKrae virus (=0·0001 and =0·0003, respectively) and CJLAT virus, containing wild-type LR in place of LAT (<0·0001) and was similar to LAT dLAT2903 (=0·8 and =0·7, respectively). Thus, disruption of BHV-1 ORF2 eliminated the high-reactivation phenotype.

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2003-11-01
2021-01-19
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References

  1. Ahmed M., Fraser N. W.. 2001; Herpes simplex virus type 1 2-kilobase latency-associated transcript intron associates with ribosomal proteins and splicing factors. J Virol75:12070–12080
    [Google Scholar]
  2. Ahmed M., Lock M., Miller C. G., Fraser N. W.. 2002; Regions of the herpes simplex virus type 1 latency-associated transcript that protect cells from apoptosis in vitro and protect neuronal cells in vivo. J Virol76:717–729
    [Google Scholar]
  3. Andreansky S., He B., van Cott J., McGhee J., Markert J. M., Gillespie G. Y., Roizman B., Whitley R. J.. 1998; Treatment of intracranial gliomas in immunocompetent mice using herpes simplex viruses that express murine interleukins. Gene Ther5:121–130
    [Google Scholar]
  4. Block T. M., Deshmane S., Masonis J., Maggioncalda J., Valyi-Nagi T., Fraser N. W.. 1993; An HSV LAT null mutant reactivates slowly from latent infection and makes small plaques on CV-1 monolayers. Virology192:618–630
    [Google Scholar]
  5. Bloom D. C., Devi-Rao G. B., Hill J. M., Stevens J. G., Wagner E. K.. 1994; Molecular analysis of herpes simplex virus type 1 during epinephrine-induced reactivation of latently infected rabbits in vivo. J Virol68:1283–1292
    [Google Scholar]
  6. Bloom D. C., Hill J. M., Devi-Rao G., Wagner E. K., Feldman L. T., Stevens J. G.. 1996; A 348-base-pair region in the latency-associated transcript facilitates herpes simplex virus type 1 reactivation. J Virol70:2449–2459
    [Google Scholar]
  7. Burton E. A., Hong C. S., Glorioso J. C.. 2003; The stable 2·0-kilobase intron of the herpes simplex virus type 1 latency-associated transcript does not function as an antisense repressor of ICP0 in nonneuronal cells. J Virol77:3516–3530
    [Google Scholar]
  8. Chen S. H., Kramer M. F., Schaffer P. A., Coen D. M.. 1997; A viral function represses accumulation of transcripts from productive-cycle genes in mouse ganglia latently infected with herpes simplex virus. J Virol71:5878–5884
    [Google Scholar]
  9. Ciacci-Zanella J., Stone M., Henderson G., Jones C.. 1999; The latency-related gene of bovine herpesvirus 1 inhibits programmed cell death. J Virol73:9734–9740
    [Google Scholar]
  10. Devi-Rao G. B., Bloom D. C., Stevens J. G., Wagner E. K.. 1994; Herpes simplex virus type 1 DNA replication and gene expression during explant-induced reactivation of latently infected murine sensory ganglia. J Virol68:1271–1282
    [Google Scholar]
  11. Devireddy L. R., Jones C.. 1998; Alternative splicing of the latency-related transcript of bovine herpesvirus 1 yields RNAs containing unique open reading frames. J Virol72:7294–7301
    [Google Scholar]
  12. Dobson A. T., Sederati F., Devi-Rao G., Flanagan W. M., Farrell M. J., Stevens J. G., Wagner E. K., Feldman L. T.. 1989; Identification of the latency-associated transcript promoter by expression of rabbit beta-globin mRNA in mouse sensory nerve ganglia latently infected with a recombinant herpes simplex virus. J Virol63:3844–3851
    [Google Scholar]
  13. Doerig C., Pizer L. I., Wilcox C. L.. 1991; An antigen encoded by the latency-associated transcript in neuronal cell cultures latently infected with herpes simplex virus type 1. J Virol65:2724–2727
    [Google Scholar]
  14. Drolet B. S., Perng G. C., Cohen J., Slanina S. M., Yukht A., Nesburn A. B., Wechsler S. L.. 1998; The region of the herpes simplex virus type 1 LAT gene involved in spontaneous reactivation does not encode a functional protein. Virology242:221–232
    [Google Scholar]
  15. Farrell M. J., Dobson A. T., Feldman L. T.. 1991; Herpes simplex virus latency-associated transcript is a stable intron. Proc Natl Acad Sci U S A88:790–794
    [Google Scholar]
  16. Garber D. A., Schaffer P. A., Knipe D. M.. 1997; A LAT-associated function reduces productive-cycle gene expression during acute infection of murine sensory neurons with herpes simplex virus type 1. J Virol71:5885–5893
    [Google Scholar]
  17. Goldenberg D., Mador N., Ball M. J., Panet A., Steiner I.. 1997; The abundant latency-associated transcripts of herpes simplex virus type 1 are bound to polyribosomes in cultured neuronal cells and during latent infection in mouse trigeminal ganglia. J Virol71:2897–2904
    [Google Scholar]
  18. Han X., Lundberg P., Tanamachi B., Openshaw H., Longmate J., Cantin E.. 2001; Gender influences herpes simplex virus type 1 infection in normal and gamma interferon-mutant mice. J Virol75:3048–3052
    [Google Scholar]
  19. Henderson G., Peng W., Jin L., Perng G. C., Nesburn A. B., Wechsler S. L., Jones C.. 2002; Regulation of caspase 8- and caspase 9-induced apoptosis by the herpes simplex virus type 1 latency-associated transcript. J Neurovirol8:Suppl 2103–111
    [Google Scholar]
  20. Hill J. M., Sedarati F., Javier R. T., Wagner E. K., Stevens J. G.. 1990; Herpes simplex virus latent phase transcription facilitates in vivo reactivation. Virology174:117–125
    [Google Scholar]
  21. Hossain A., Schang L. M., Jones C.. 1995; Identification of gene products encoded by the latency-related gene of bovine herpesvirus 1. J Virol69:5345–5352
    [Google Scholar]
  22. Inman M., Lovato L., Doster A., Jones C.. 2001a; A mutation in the latency-related gene of bovine herpesvirus 1 leads to impaired ocular shedding in acutely infected calves. J Virol75:8507–8515
    [Google Scholar]
  23. Inman M., Perng G. C., Henderson G., Ghiasi H., Nesburn A. B., Wechsler S. L., Jones C.. 2001b; Region of herpes simplex virus type 1 latency-associated transcript sufficient for wild-type spontaneous reactivation promotes cell survival in tissue culture. J Virol75:3636–3646
    [Google Scholar]
  24. Inman M., Lovato L., Doster A., Jones C.. 2002; A mutation in the latency-related gene of bovine herpesvirus 1 disrupts the latency reactivation cycle in calves. J Virol76:6771–6779
    [Google Scholar]
  25. Jackwood M. W.. 2000; Analysis of latency in cattle after inoculation with a temperature sensitive mutant of bovine herpesvirus 1 (RLB106). . : Vaccine 18:3185–3195
    [Google Scholar]
  26. Jiang Y., Hossain A., Winkler M. T., Holt T., Doster A., Jones C.. 1998; A protein encoded by the latency-related gene of bovine herpesvirus 1 is expressed in trigeminal ganglionic neurons of latently infected cattle and interacts with cyclin-dependent kinase 2 during productive infection. J Virol72:8133–8142
    [Google Scholar]
  27. Jin L., Peng W., Perng G. C., Brick D. J., Nesburn A. B., Jones C., Wechsler S. L.. 2003; Identification of herpes simplex virus type 1 latency-associated transcript sequences that both inhibit apoptosis and enhance the spontaneous reactivation phenotype. J Virol77:6556–6561
    [Google Scholar]
  28. Jones C., Newby T. J., Holt T.. 8 other authors 2001; FLICE-inhibitory proteins: regulators of death receptor-mediated apoptosis. Mol Cell Biol21:8247–8254
    [Google Scholar]
  29. Kutish G., Mainprize T., Rock D.. 1990; Characterization of the latency-related transcriptionally active region of the bovine herpesvirus 1 genome. J Virol64:5730–5737
    [Google Scholar]
  30. Leib D. A., Bogard C. L., Kosz-Vnenchak M., Hicks K. A., Coen D. M., Knipe D. M., Schaffer P. A.. 1989; A deletion mutant of the latency-associated transcript of herpes simplex virus type 1 reactivates from the latent state with reduced frequency. J Virol63:2893–2900
    [Google Scholar]
  31. Liesegang T. J., Melton L. J. III, Daly P. J., Ilstrup D. M.. 1989; Epidemiology of ocular herpes simplex. Incidence in Rochester, Minn, 1950 through 1982. Arch Ophthalmol107:1155–1159
    [Google Scholar]
  32. Lovato L., Inman M., Henderson G., Doster A., Jones C.. 2003; Infection of cattle with a bovine herpesvirus 1 strain that contains a mutation in the latency-related gene leads to increased apoptosis in trigeminal ganglia during the transition from acute infection to latency. J Virol77:4848–4857
    [Google Scholar]
  33. Perng G. C., Dunkel E. C., Geary P. A., Slanina S. M., Ghiasi H., Kaiwar R., Nesburn A. B., Wechsler S. L.. 1994; The latency-associated transcript gene of herpes simplex virus type 1 (HSV-1) is required for efficient in vivo spontaneous reactivation of HSV-1 from latency. J Virol68:8045–8055
    [Google Scholar]
  34. Perng G. C., Ghiasi H., Slanina S. M., Nesburn A. B., Wechsler S. L.. 1996; The spontaneous reactivation function of the herpes simplex virus type 1 LAT gene resides completely within the first 1·5 kilobases of the 8·3-kilobase primary transcript. J Virol70:976–984
    [Google Scholar]
  35. Perng G. C., Slanina S. M., Yukht A., Drolet B. S., Keleher W. Jr, Ghiasi H., Nesburn A. B., Wechsler S. L.. 1999a; A herpes simplex virus type 1 latency-associated transcript mutant with increased virulence and reduced spontaneous reactivation. J Virol73:920–929
    [Google Scholar]
  36. Perng G. C., Slanina S. M., Yukht A., Ghiasi H., Nesburn A. B., Wechsler S. L.. 1999b; Herpes simplex virus type 1 serum neutralizing antibody titers increase during latency in rabbits latently infected with latency-associated transcript (LAT)-positive but not LAT-negative viruses. J Virol73:9669–9672
    [Google Scholar]
  37. Perng G. C., Jones C., Ciacci-Zanella J.. & 8 other authors (2000a). Virus-induced neuronal apoptosis blocked by the herpes simplex virus latency-associated transcript. Science287:1500–1503
    [Google Scholar]
  38. Perng G. C., Slanina S. M., Yukht A., Ghiasi H., Nesburn A. B., Wechsler S. L.. 2000b; The latency-associated transcript gene enhances establishment of herpes simplex virus type 1 latency in rabbits. J Virol74:1885–1891
    [Google Scholar]
  39. Perng G. C., Esmaili D., Slanina S. M.. 8 other authors 2001a; Three herpes simplex virus type 1 latency-associated transcript mutants with distinct and asymmetric effects on virulence in mice compared with rabbits. J Virol75:9018–9028
    [Google Scholar]
  40. Perng G. C., Slanina S. M., Ghiasi H., Nesburn A. B., Wechsler S. L.. 2001b; The effect of latency-associated transcript on the herpes simplex virus type 1 latency-reactivation phenotype is mouse strain-dependent. J Gen Virol82:1117–1122
    [Google Scholar]
  41. Perng G. C., Maguen B., Jin L.. 10 other authors 2002; A gene capable of blocking apoptosis can substitute for the herpes simplex virus type 1 latency-associated transcript gene and restore wild-type reactivation levels. J Virol76:1224–1235
    [Google Scholar]
  42. Rock D. L., Beam S. L., Mayfield J. E.. 1987a; Mapping bovine herpesvirus type 1 latency-related RNA in trigeminal ganglia of latently infected rabbits. J Virol61:3827–3831
    [Google Scholar]
  43. Rock D. L., Nesburn A. B., Ghiasi H., Ong J., Lewis T. L., Lokensgard J. R., Wechsler S. L.. 1987b; Detection of latency-related viral RNAs in trigeminal ganglia of rabbits latently infected with herpes simplex virus type 1. J Virol61:3820–3826
    [Google Scholar]
  44. Rock D., Lokensgard J., Lewis T., Kutish G.. 1992; Characterization of dexamethasone-induced reactivation of latent bovine herpesvirus 1. J Virol66:2484–2490
    [Google Scholar]
  45. Roizman B., Whitley R. J.. 2001; The nine ages of herpes simplex virus. Herpes8:23–27
    [Google Scholar]
  46. Sawtell N. M.. 1997; Comprehensive quantification of herpes simplex virus latency at the single-cell level. J Virol71:5423–5431
    [Google Scholar]
  47. Sawtell N. M., Thompson R. L.. 1992; Herpes simplex virus type 1 latency-associated transcription unit promotes anatomical site-dependent establishment and reactivation from latency. J Virol66:2157–2169
    [Google Scholar]
  48. Schmitz I., Kirchhoff S., Krammer P. H.. 2000; Regulation of death receptor-mediated apoptosis pathways. Int J Biochem Cell Biol32:1123–1136
    [Google Scholar]
  49. Spivack J. G., Fraser N. W.. 1988; Expression of herpes simplex virus type 1 (HSV-1) latency-associated transcripts and transcripts affected by the deletion in avirulent mutant HFEM: evidence for a new class of HSV-1 genes. J Virol62:3281–3287
    [Google Scholar]
  50. Steiner I., Spivack J. G., Lirette R. P., Brown S. M., MacLean A. R., Subak-Sharpe J. H., Fraser N. W.. 1989; Herpes simplex virus type 1 latency-associated transcripts are evidently not essential for latent infection. EMBO J8:505–511
    [Google Scholar]
  51. Stevens J. G.. 1990; Transcripts associated with herpes simplex virus latency. Adv Exp Med Biol278:199–204
    [Google Scholar]
  52. Stevens J. G., Wagner E. K., Devi-Rao G. B., Cook M. L., Feldman L. T.. 1987; RNA complementary to a herpesvirus alpha gene mRNA is prominent in latently infected neurons. Science235:1056–1059
    [Google Scholar]
  53. Thomas S. K., Gough G., Latchman D. S., Coffin R. S.. 1999; Herpes simplex virus latency-associated transcript encodes a protein which greatly enhances virus growth, can compensate for deficiencies in immediate-early gene expression, and is likely to function during reactivation from virus latency. J Virol73:6618–6625
    [Google Scholar]
  54. Thomas S. K., Lilley C. E., Latchman D. S., Coffin R. S.. 2002; A protein encoded by the herpes simplex virus (HSV) type 1 2-kilobase latency-associated transcript is phosphorylated, localized to the nucleus, and overcomes the repression of expression from exogenous promoters when inserted into the quiescent HSV genome. J Virol76:4056–4067
    [Google Scholar]
  55. Thompson R. L., Sawtell N. M.. 1997; The herpes simplex virus type 1 latency-associated transcript gene regulates the establishment of latency. J Virol71:5432–5440
    [Google Scholar]
  56. Thompson R. L., Sawtell N. M.. 2001; Herpes simplex virus type 1 latency-associated transcript gene promotes neuronal survival. J Virol75:6660–6675
    [Google Scholar]
  57. Wang X.. 2001; The expanding role of mitochondria in apoptosis. Genes Dev15:2922–2933
    [Google Scholar]
  58. Wechsler S. L., Nesburn A. B., Watson R., Slanina S. M., Ghiasi H.. 1988; Fine mapping of the latency-related gene of herpes simplex virus type 1: alternative splicing produces distinct latency-related RNAs containing open reading frames. J Virol62:4051–4058
    [Google Scholar]
  59. Wechsler S. L., Nesburn A. B., Zwaagstra J., Ghiasi H.. 1989; Sequence of the latency-related gene of herpes simplex virus type 1. Virology168:168–172
    [Google Scholar]
  60. Zwaagstra J., Ghiasi H., Nesburn A. B., Wechsler S. L.. 1989; In vitro promoter activity associated with the latency-associated transcript gene of herpes simplex virus type 1. J Gen Virol70:2163–2169
    [Google Scholar]
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