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
2019-12-05
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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 Virol 75, 12070–12080.[CrossRef]
    [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 Virol 76, 717–729.[CrossRef]
    [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 Ther 5, 121–130.[CrossRef]
    [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. Virology 192, 618–630.[CrossRef]
    [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 Virol 68, 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 Virol 70, 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 Virol 77, 3516–3530.[CrossRef]
    [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 Virol 71, 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 Virol 73, 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 Virol 68, 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 Virol 72, 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 Virol 63, 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 Virol 65, 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. Virology 242, 221–232.[CrossRef]
    [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 A 88, 790–794.[CrossRef]
    [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 Virol 71, 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 Virol 71, 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 Virol 75, 3048–3052.[CrossRef]
    [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 Neurovirol 8(Suppl 2), 103–111.[CrossRef]
    [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. Virology 174, 117–125.[CrossRef]
    [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 Virol 69, 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 Virol 75, 8507–8515.[CrossRef]
    [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 Virol 75, 3636–3646.[CrossRef]
    [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 Virol 76, 6771–6779.[CrossRef]
    [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.[CrossRef]
    [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 Virol 72, 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 Virol 77, 6556–6561.[CrossRef]
    [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 Biol 21, 8247–8254.[CrossRef]
    [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 Virol 64, 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 Virol 63, 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 Ophthalmol 107, 1155–1159.[CrossRef]
    [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 Virol 77, 4848–4857.[CrossRef]
    [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 Virol 68, 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 Virol 70, 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 Virol 73, 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 Virol 73, 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. Science 287, 1500–1503.[CrossRef]
    [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 Virol 74, 1885–1891.[CrossRef]
    [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 Virol 75, 9018–9028.[CrossRef]
    [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 Virol 82, 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 Virol 76, 1224–1235.[CrossRef]
    [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 Virol 61, 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 Virol 61, 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 Virol 66, 2484–2490.
    [Google Scholar]
  45. Roizman, B. & Whitley, R. J. ( 2001; ). The nine ages of herpes simplex virus. Herpes 8, 23–27.
    [Google Scholar]
  46. Sawtell, N. M. ( 1997; ). Comprehensive quantification of herpes simplex virus latency at the single-cell level. J Virol 71, 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 Virol 66, 2157–2169.
    [Google Scholar]
  48. Schmitz, I., Kirchhoff, S. & Krammer, P. H. ( 2000; ). Regulation of death receptor-mediated apoptosis pathways. Int J Biochem Cell Biol 32, 1123–1136.[CrossRef]
    [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 Virol 62, 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 J 8, 505–511.
    [Google Scholar]
  51. Stevens, J. G. ( 1990; ). Transcripts associated with herpes simplex virus latency. Adv Exp Med Biol 278, 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. Science 235, 1056–1059.[CrossRef]
    [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 Virol 73, 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 Virol 76, 4056–4067.[CrossRef]
    [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 Virol 71, 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 Virol 75, 6660–6675.[CrossRef]
    [Google Scholar]
  57. Wang, X. ( 2001; ). The expanding role of mitochondria in apoptosis. Genes Dev 15, 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 Virol 62, 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. Virology 168, 168–172.[CrossRef]
    [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 Virol 70, 2163–2169.[CrossRef]
    [Google Scholar]
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