Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1991 Jun;65(6):2929–2935. doi: 10.1128/jvi.65.6.2929-2935.1991

Expression of the herpes simplex virus 1 alpha transinducing factor (VP16) does not induce reactivation of latent virus or prevent the establishment of latency in mice.

A E Sears 1, V Hukkanen 1, M A Labow 1, A J Levine 1, B Roizman 1
PMCID: PMC240928  PMID: 1851865

Abstract

A feature of the cascade regulation of herpes simplex virus 1 gene expression in productive infection is that the first genes to be expressed, the alpha genes, are transactivated by a structural component of the virion designated as the alpha transinducing factor (alpha TIF). In this study, we have tested the hypothesis that latent infection of sensory neurons results from the failure of alpha TIF, a tegument protein, to be transported from the nerve endings to the nucleus of the sensory neuron. Two viruses were constructed. The first recombinant virus (R6003) contained a second copy of the alpha TIF gene placed under the control of a metallothionein promoter. The second recombinant virus (R6004) is identical to R6003 except for the presence of a stop codon inserted at amino acid 70 of the second alpha TIF gene. The metallothionein promoter inserted into the viral genome was shown to be expressed, and alpha TIF mRNA was detected by in situ hybridization of sections of trigeminal ganglia of mice infected with R6003, both untreated and those given cadmium injections. In all experiments, there were no significant differences in the recovery of latent virus from mice infected with R6003 or R6004, whether injected with cadmium or not. Cadmium administration at the time of infection and at intervals thereafter did not preclude establishment of latency. In another series of experiments, transgenic mice expressing the metallothionein-driven alpha TIF did not differ from nontransgenic siblings with respect to the incidence of latent virus in trigeminal ganglia. We conclude that the absence of alpha TIF cannot alone account for the establishment of latency.

Full text

PDF
2933

Images in this article

2933Image
on p.2933

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Augusti-Tocco G., Sato G. Establishment of functional clonal lines of neurons from mouse neuroblastoma. Proc Natl Acad Sci U S A. 1969 Sep;64(1):311–315. doi: 10.1073/pnas.64.1.311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Batterson W., Furlong D., Roizman B. Molecular genetics of herpes simplex virus. VIII. further characterization of a temperature-sensitive mutant defective in release of viral DNA and in other stages of the viral reproductive cycle. J Virol. 1983 Jan;45(1):397–407. doi: 10.1128/jvi.45.1.397-407.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Batterson W., Roizman B. Characterization of the herpes simplex virion-associated factor responsible for the induction of alpha genes. J Virol. 1983 May;46(2):371–377. doi: 10.1128/jvi.46.2.371-377.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brinster R. L., Chen H. Y., Warren R., Sarthy A., Palmiter R. D. Regulation of metallothionein--thymidine kinase fusion plasmids injected into mouse eggs. Nature. 1982 Mar 4;296(5852):39–42. doi: 10.1038/296039a0. [DOI] [PubMed] [Google Scholar]
  5. Campione-Piccardo J., Rawls W. E., Bacchetti S. Selective assay for herpes simplex viruses expressing thymidine kinase. J Virol. 1979 Aug;31(2):281–287. doi: 10.1128/jvi.31.2.281-287.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Coen D. M., Kosz-Vnenchak M., Jacobson J. G., Leib D. A., Bogard C. L., Schaffer P. A., Tyler K. L., Knipe D. M. Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4736–4740. doi: 10.1073/pnas.86.12.4736. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Durnam D. M., Palmiter R. D. Transcriptional regulation of the mouse metallothionein-I gene by heavy metals. J Biol Chem. 1981 Jun 10;256(11):5712–5716. [PubMed] [Google Scholar]
  8. Gerster T., Roeder R. G. A herpesvirus trans-activating protein interacts with transcription factor OTF-1 and other cellular proteins. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6347–6351. doi: 10.1073/pnas.85.17.6347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gordon Y. J., Johnson B., Romanowski E., Araullo-Cruz T. RNA complementary to herpes simplex virus type 1 ICP0 gene demonstrated in neurons of human trigeminal ganglia. J Virol. 1988 May;62(5):1832–1835. doi: 10.1128/jvi.62.5.1832-1835.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Harbour D. A., Hill T. J., Blyth W. A. Recurrent herpes simplex in the mouse: inflammation in the skin and activation of virus in the ganglia following peripheral stimulation. J Gen Virol. 1983 Jul;64(Pt 7):1491–1498. doi: 10.1099/0022-1317-64-7-1491. [DOI] [PubMed] [Google Scholar]
  11. He X., Treacy M. N., Simmons D. M., Ingraham H. A., Swanson L. W., Rosenfeld M. G. Expression of a large family of POU-domain regulatory genes in mammalian brain development. Nature. 1989 Jul 6;340(6228):35–41. doi: 10.1038/340035a0. [DOI] [PubMed] [Google Scholar]
  12. Heine J. W., Honess R. W., Cassai E., Roizman B. Proteins specified by herpes simplex virus. XII. The virion polypeptides of type 1 strains. J Virol. 1974 Sep;14(3):640–651. doi: 10.1128/jvi.14.3.640-651.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Heine J. W., Spear P. G., Roizman B. Proteins specified by herpes simplex virus. VI. Viral proteins in the plasma membrane. J Virol. 1972 Mar;9(3):431–439. doi: 10.1128/jvi.9.3.431-439.1972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Honess R. W., Roizman B. Regulation of herpesvirus macromolecular synthesis. I. Cascade regulation of the synthesis of three groups of viral proteins. J Virol. 1974 Jul;14(1):8–19. doi: 10.1128/jvi.14.1.8-19.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Honess R. W., Roizman B. Regulation of herpesvirus macromolecular synthesis: sequential transition of polypeptide synthesis requires functional viral polypeptides. Proc Natl Acad Sci U S A. 1975 Apr;72(4):1276–1280. doi: 10.1073/pnas.72.4.1276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jacobson J. G., Leib D. A., Goldstein D. J., Bogard C. L., Schaffer P. A., Weller S. K., Coen D. M. 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. 1989 Nov;173(1):276–283. doi: 10.1016/0042-6822(89)90244-4. [DOI] [PubMed] [Google Scholar]
  17. Javier R. T., Stevens J. G., Dissette V. B., Wagner E. K. A herpes simplex virus transcript abundant in latently infected neurons is dispensable for establishment of the latent state. Virology. 1988 Sep;166(1):254–257. doi: 10.1016/0042-6822(88)90169-9. [DOI] [PubMed] [Google Scholar]
  18. Katz J. P., Bodin E. T., Coen D. M. Quantitative polymerase chain reaction analysis of herpes simplex virus DNA in ganglia of mice infected with replication-incompetent mutants. J Virol. 1990 Sep;64(9):4288–4295. doi: 10.1128/jvi.64.9.4288-4295.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kemp L. M., Dent C. L., Latchman D. S. Octamer motif mediates transcriptional repression of HSV immediate-early genes and octamer-containing cellular promoters in neuronal cells. Neuron. 1990 Feb;4(2):215–222. doi: 10.1016/0896-6273(90)90096-x. [DOI] [PubMed] [Google Scholar]
  20. Kristie T. M., Roizman B. Differentiation and DNA contact points of host proteins binding at the cis site for virion-mediated induction of alpha genes of herpes simplex virus 1. J Virol. 1988 Apr;62(4):1145–1157. doi: 10.1128/jvi.62.4.1145-1157.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kristie T. M., Roizman B. Host cell proteins bind to the cis-acting site required for virion-mediated induction of herpes simplex virus 1 alpha genes. Proc Natl Acad Sci U S A. 1987 Jan;84(1):71–75. doi: 10.1073/pnas.84.1.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kristie T. M., Roizman B. Separation of sequences defining basal expression from those conferring alpha gene recognition within the regulatory domains of herpes simplex virus 1 alpha genes. Proc Natl Acad Sci U S A. 1984 Jul;81(13):4065–4069. doi: 10.1073/pnas.81.13.4065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Leib D. A., Coen D. M., Bogard C. L., Hicks K. A., Yager D. R., Knipe D. M., Tyler K. L., Schaffer P. A. Immediate-early regulatory gene mutants define different stages in the establishment and reactivation of herpes simplex virus latency. J Virol. 1989 Feb;63(2):759–768. doi: 10.1128/jvi.63.2.759-768.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mackem S., Roizman B. Structural features of the herpes simplex virus alpha gene 4, 0, and 27 promoter-regulatory sequences which confer alpha regulation on chimeric thymidine kinase genes. J Virol. 1982 Dec;44(3):939–949. doi: 10.1128/jvi.44.3.939-949.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Maples J. A. A method for the covalent attachment of cells to glass slides for use in immunohistochemical assays. Am J Clin Pathol. 1985 Mar;83(3):356–363. doi: 10.1093/ajcp/83.3.356. [DOI] [PubMed] [Google Scholar]
  26. Meignier B., Longnecker R., Mavromara-Nazos P., Sears A. E., Roizman B. Virulence of and establishment of latency by genetically engineered deletion mutants of herpes simplex virus 1. Virology. 1988 Jan;162(1):251–254. doi: 10.1016/0042-6822(88)90417-5. [DOI] [PubMed] [Google Scholar]
  27. O'Hare P., Goding C. R. Herpes simplex virus regulatory elements and the immunoglobulin octamer domain bind a common factor and are both targets for virion transactivation. Cell. 1988 Feb 12;52(3):435–445. doi: 10.1016/s0092-8674(88)80036-9. [DOI] [PubMed] [Google Scholar]
  28. O'Neill E. A., Fletcher C., Burrow C. R., Heintz N., Roeder R. G., Kelly T. J. Transcription factor OTF-1 is functionally identical to the DNA replication factor NF-III. Science. 1988 Sep 2;241(4870):1210–1213. doi: 10.1126/science.3413485. [DOI] [PubMed] [Google Scholar]
  29. Palmiter R. D., Chen H. Y., Brinster R. L. Differential regulation of metallothionein-thymidine kinase fusion genes in transgenic mice and their offspring. Cell. 1982 Jun;29(2):701–710. doi: 10.1016/0092-8674(82)90186-6. [DOI] [PubMed] [Google Scholar]
  30. Pellett P. E., McKnight J. L., Jenkins F. J., Roizman B. Nucleotide sequence and predicted amino acid sequence of a protein encoded in a small herpes simplex virus DNA fragment capable of trans-inducing alpha genes. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5870–5874. doi: 10.1073/pnas.82.17.5870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Poffenberger K. L., Roizman B. A noninverting genome of a viable herpes simplex virus 1: presence of head-to-tail linkages in packaged genomes and requirements for circularization after infection. J Virol. 1985 Feb;53(2):587–595. doi: 10.1128/jvi.53.2.587-595.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Post L. E., Mackem S., Roizman B. Regulation of alpha genes of herpes simplex virus: expression of chimeric genes produced by fusion of thymidine kinase with alpha gene promoters. Cell. 1981 May;24(2):555–565. doi: 10.1016/0092-8674(81)90346-9. [DOI] [PubMed] [Google Scholar]
  33. Roizman B., Sears A. E. An inquiry into the mechanisms of herpes simplex virus latency. Annu Rev Microbiol. 1987;41:543–571. doi: 10.1146/annurev.mi.41.100187.002551. [DOI] [PubMed] [Google Scholar]
  34. Sears A. E., Halliburton I. W., Meignier B., Silver S., Roizman B. Herpes simplex virus 1 mutant deleted in the alpha 22 gene: growth and gene expression in permissive and restrictive cells and establishment of latency in mice. J Virol. 1985 Aug;55(2):338–346. doi: 10.1128/jvi.55.2.338-346.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sears A. E., Meignier B., Roizman B. Establishment of latency in mice by herpes simplex virus 1 recombinants that carry insertions affecting regulation of the thymidine kinase gene. J Virol. 1985 Aug;55(2):410–416. doi: 10.1128/jvi.55.2.410-416.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Stevens J. G., Wagner E. K., Devi-Rao G. B., Cook M. L., Feldman L. T. RNA complementary to a herpesvirus alpha gene mRNA is prominent in latently infected neurons. Science. 1987 Feb 27;235(4792):1056–1059. doi: 10.1126/science.2434993. [DOI] [PubMed] [Google Scholar]
  37. Weber P. C., Levine M., Glorioso J. C. Rapid identification of nonessential genes of herpes simplex virus type 1 by Tn5 mutagenesis. Science. 1987 May 1;236(4801):576–579. doi: 10.1126/science.3033824. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES