Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1996 Aug;70(8):5476–5486. doi: 10.1128/jvi.70.8.5476-5486.1996

Herpes simplex virus gene expression in neurons: viral DNA synthesis is a critical regulatory event in the branch point between the lytic and latent pathways.

P F Nichol 1, J Y Chang 1, E M Johnson Jr 1, P D Olivo 1
PMCID: PMC190505  PMID: 8764059

Abstract

Herpes simplex virus establishes a latent infection in peripheral neurons. We examined viral gene expression in rat peripheral neurons in vitro and determined that viral gene expression is attenuated and delayed in these neurons compared with that in Vero cells. In addition, using pharmacologic and genetic blocks to viral DNA synthesis, we found that viral alpha and beta gene expression was upregulated by viral DNA synthesis. Although maximal gene expression in neurons requires viral DNA synthetic activity, activation of viral gene expression was seen even in the presence of herpes simplex virus DNA polymerase inhibitors, but not in the absence of the origin-binding protein. Initiation of viral DNA synthesis is apparently a key regulatory event in the balance between the lytic and latent pathways in peripheral neurons.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

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

  1. ANDERSON W. A., MARGRUDER B., KILBOURNE E. D. Induced reactivation of herpes simplex virus in healed rabbit corneal lesions. Proc Soc Exp Biol Med. 1961 Jul;107:628–632. doi: 10.3181/00379727-107-26709. [DOI] [PubMed] [Google Scholar]
  2. Blyth W. A., Hill T. J., Field H. J., Harbour D. A. Reactivation of herpes simplex virus infection by ultraviolet light and possible involvement of prostaglandins. J Gen Virol. 1976 Dec;33(3):547–550. doi: 10.1099/0022-1317-33-3-547. [DOI] [PubMed] [Google Scholar]
  3. Bocchini V., Angeletti P. U. The nerve growth factor: purification as a 30,000-molecular-weight protein. Proc Natl Acad Sci U S A. 1969 Oct;64(2):787–794. doi: 10.1073/pnas.64.2.787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bruckner R. C., Crute J. J., Dodson M. S., Lehman I. R. The herpes simplex virus 1 origin binding protein: a DNA helicase. J Biol Chem. 1991 Feb 5;266(4):2669–2674. [PubMed] [Google Scholar]
  5. Challberg M. D., Kelly T. J. Animal virus DNA replication. Annu Rev Biochem. 1989;58:671–717. doi: 10.1146/annurev.bi.58.070189.003323. [DOI] [PubMed] [Google Scholar]
  6. Chang J. Y., Johnson E. M., Jr, Olivo P. D. A gene delivery/recall system for neurons which utilizes ribonucleotide reductase-negative herpes simplex viruses. Virology. 1991 Nov;185(1):437–440. doi: 10.1016/0042-6822(91)90794-c. [DOI] [PubMed] [Google Scholar]
  7. Deb S. P., Deb S., Brown D. R. Cell-type-specific induction of the UL9 gene of HSV-1 by cell signaling pathway. Biochem Biophys Res Commun. 1994 Nov 30;205(1):44–51. doi: 10.1006/bbrc.1994.2627. [DOI] [PubMed] [Google Scholar]
  8. Estus S., Zaks W. J., Freeman R. S., Gruda M., Bravo R., Johnson E. M., Jr Altered gene expression in neurons during programmed cell death: identification of c-jun as necessary for neuronal apoptosis. J Cell Biol. 1994 Dec;127(6 Pt 1):1717–1727. doi: 10.1083/jcb.127.6.1717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gao M., Matusick-Kumar L., Hurlburt W., DiTusa S. F., Newcomb W. W., Brown J. C., McCann P. J., 3rd, Deckman I., Colonno R. J. The protease of herpes simplex virus type 1 is essential for functional capsid formation and viral growth. J Virol. 1994 Jun;68(6):3702–3712. doi: 10.1128/jvi.68.6.3702-3712.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Garcia-Blanco M. A., Cullen B. R. Molecular basis of latency in pathogenic human viruses. Science. 1991 Nov 8;254(5033):815–820. doi: 10.1126/science.1658933. [DOI] [PubMed] [Google Scholar]
  11. Goldstein D. J., Weller S. K. Herpes simplex virus type 1-induced ribonucleotide reductase activity is dispensable for virus growth and DNA synthesis: isolation and characterization of an ICP6 lacZ insertion mutant. J Virol. 1988 Jan;62(1):196–205. doi: 10.1128/jvi.62.1.196-205.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hagmann M., Georgiev O., Schaffner W., Douville P. Transcription factors interacting with herpes simplex virus alpha gene promoters in sensory neurons. Nucleic Acids Res. 1995 Dec 25;23(24):4978–4985. doi: 10.1093/nar/23.24.4978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Harris-Hamilton E., Bachenheimer S. L. Accumulation of herpes simplex virus type 1 RNAs of different kinetic classes in the cytoplasm of infected cells. J Virol. 1985 Jan;53(1):144–151. doi: 10.1128/jvi.53.1.144-151.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. Honess R. W., Roizman B. Proteins specified by herpes simplex virus. XI. Identification and relative molar rates of synthesis of structural and nonstructural herpes virus polypeptides in the infected cell. J Virol. 1973 Dec;12(6):1347–1365. doi: 10.1128/jvi.12.6.1347-1365.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Honess R. W., Roizman B. Proteins specified by herpes simplex virus. XIII. Glycosylation of viral polypeptides. J Virol. 1975 Nov;16(5):1308–1326. doi: 10.1128/jvi.16.5.1308-1326.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. 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]
  19. Kosz-Vnenchak M., Coen D. M., Knipe D. M. Restricted expression of herpes simplex virus lytic genes during establishment of latent infection by thymidine kinase-negative mutant viruses. J Virol. 1990 Nov;64(11):5396–5402. doi: 10.1128/jvi.64.11.5396-5402.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kosz-Vnenchak M., Jacobson J., Coen D. M., Knipe D. M. Evidence for a novel regulatory pathway for herpes simplex virus gene expression in trigeminal ganglion neurons. J Virol. 1993 Sep;67(9):5383–5393. doi: 10.1128/jvi.67.9.5383-5393.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. Leist T. P., Sandri-Goldin R. M., Stevens J. G. Latent infections in spinal ganglia with thymidine kinase-deficient herpes simplex virus. J Virol. 1989 Nov;63(11):4976–4978. doi: 10.1128/jvi.63.11.4976-4978.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Malik A. K., Martinez R., Muncy L., Carmichael E. P., Weller S. K. Genetic analysis of the herpes simplex virus type 1 UL9 gene: isolation of a LacZ insertion mutant and expression in eukaryotic cells. Virology. 1992 Oct;190(2):702–715. doi: 10.1016/0042-6822(92)90908-8. [DOI] [PubMed] [Google Scholar]
  24. Nichol P. F., Chang J. Y., Johnson E. M., Jr, Olivo P. D. Infection of sympathetic and sensory neurones with herpes simplex virus does not elicit a shut-off of cellular protein synthesis: implications for viral latency and herpes vectors. Neurobiol Dis. 1994 Nov;1(1-2):83–94. doi: 10.1006/nbdi.1994.0011. [DOI] [PubMed] [Google Scholar]
  25. Olivo P. D., Nelson N. J., Challberg M. D. Herpes simplex virus type 1 gene products required for DNA replication: identification and overexpression. J Virol. 1989 Jan;63(1):196–204. doi: 10.1128/jvi.63.1.196-204.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Perna J. J., Mannix M. L., Rooney J. F., Notkins A. L., Straus S. E. Reactivation of latent herpes simplex virus infection by ultraviolet light: a human model. J Am Acad Dermatol. 1987 Sep;17(3):473–478. doi: 10.1016/s0190-9622(87)70232-1. [DOI] [PubMed] [Google Scholar]
  27. Polvino-Bodnar M., Orberg P. K., Schaffer P. A. Herpes simplex virus type 1 oriL is not required for virus replication or for the establishment and reactivation of latent infection in mice. J Virol. 1987 Nov;61(11):3528–3535. doi: 10.1128/jvi.61.11.3528-3535.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rafield L. F., Knipe D. M. Characterization of the major mRNAs transcribed from the genes for glycoprotein B and DNA-binding protein ICP8 of herpes simplex virus type 1. J Virol. 1984 Mar;49(3):960–969. doi: 10.1128/jvi.49.3.960-969.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sanes J. R., Rubenstein J. L., Nicolas J. F. Use of a recombinant retrovirus to study post-implantation cell lineage in mouse embryos. EMBO J. 1986 Dec 1;5(12):3133–3142. doi: 10.1002/j.1460-2075.1986.tb04620.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sawtell N. M., Thompson R. L. Rapid in vivo reactivation of herpes simplex virus in latently infected murine ganglionic neurons after transient hyperthermia. J Virol. 1992 Apr;66(4):2150–2156. doi: 10.1128/jvi.66.4.2150-2156.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Smith R. L., Pizer L. I., Johnson E. M., Jr, Wilcox C. L. Activation of second-messenger pathways reactivates latent herpes simplex virus in neuronal cultures. Virology. 1992 May;188(1):311–318. doi: 10.1016/0042-6822(92)90760-m. [DOI] [PubMed] [Google Scholar]
  32. Spear P. G., Kellejmroian B. Proteins spcified by herpes simplex virus. II. Viral glycoprotins associated with cellular membranes. J Virol. 1970 Feb;5(2):123–131. doi: 10.1128/jvi.5.2.123-131.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Tenser R. B., Edris W. A., Hay K. A. Herpes simplex virus latent infection: reactivation and elimination of latency after neurectomy. Virology. 1988 Nov;167(1):302–305. doi: 10.1016/0042-6822(88)90085-2. [DOI] [PubMed] [Google Scholar]
  34. Wilcox C. L., Crnic L. S., Pizer L. I. Replication, latent infection, and reactivation in neuronal culture with a herpes simplex virus thymidine kinase-negative mutant. Virology. 1992 Mar;187(1):348–352. doi: 10.1016/0042-6822(92)90326-k. [DOI] [PubMed] [Google Scholar]
  35. Wilcox C. L., Johnson E. M., Jr Characterization of nerve growth factor-dependent herpes simplex virus latency in neurons in vitro. J Virol. 1988 Feb;62(2):393–399. doi: 10.1128/jvi.62.2.393-399.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wilcox C. L., Johnson E. M., Jr Nerve growth factor deprivation results in the reactivation of latent herpes simplex virus in vitro. J Virol. 1987 Jul;61(7):2311–2315. doi: 10.1128/jvi.61.7.2311-2315.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Wilcox C. L., Smith R. L., Freed C. R., Johnson E. M., Jr Nerve growth factor-dependence of herpes simplex virus latency in peripheral sympathetic and sensory neurons in vitro. J Neurosci. 1990 Apr;10(4):1268–1275. doi: 10.1523/JNEUROSCI.10-04-01268.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES