The role of varicella zoster virus immediate-early proteins in latency and their potential use as components of vaccines

  • C. Sadzot-Delvaux
  • B. Rentier
Conference paper


Varicella zoster virus im-early (IE) proteins are intracellular regulators of viral gene expression. Some of them (1E62 and 1E63) are found in large amounts in infected cells but are also components of the virion tegument. Several IE and early genes are transcribed during latency, while late genes are not. Recently, we demonstrated the presence of protein IE 63 in dorsal root ganglia of persistently infected rats as well as in normal human ganglia; other IE proteins have been found since in human ganglia. Cell-mediated immunity (CMI) to IE 62 has been evidenced. We found both humoral immunity and CMI to IE 63 in immune adults. In elderly zoster-free individuals, CMI to IE 63 remained high. The differences in the CMI to IE 63 among young adults, elderly people and immunocompromized patients have to be analyzed according to their status relative to zoster, to determine whether the decrease in CMI, particularly to IE proteins, could be responsible for viral reactivation and for the onset of shingles. Hopefully, the waning of the CMI to VZV IE 63 and perhaps to other IE proteins could become a predictive marker for herpes zoster and reimmunization, not only with the vaccine strain, but also with purified IE proteins could help prevent zoster at old age.


Herpes Zoster Varicella Zoster Virus Viral Reactivation Viral Tegument Human Trigeminal Ganglion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Ahn K, Meyer TH, Uebel S, Sempe S, Djaballah H, Yang Y, Peterson PA, Fruh K, Tampe R (1996) Molecular mechanism and species specificity of TAP inhibition by herpes simplex virus ICP47. EMBO J 15: 3247–3255PubMedGoogle Scholar
  2. 2.
    Arvin AM, Kinney-Thomas E, Shriver K, Grose C, Koropchak CM, Scranton E, Wittek AE, Diaz PS (1986) Immunity to varicella-zoster viral glycoproteins, gp I (gp 90/58) and gp III (gp 118), and to a nonglycosylated protein, p 170. J Immunol 137: 1346–1351PubMedGoogle Scholar
  3. 3.
    Arvin AM, Pollard RB, Ramussen LE, Merigan TC (1980) Cellular and humoral immunity in lymphoma patients. J Clin Invest 65: 869PubMedCrossRefGoogle Scholar
  4. 4.
    Arvin AM, Sharp M, Smith S, Koropchak CM, Diaz PS, Kinchongton P, Ruyechan W (1991) Equivalent recognition of a varicella-zoster virus immediate early protein (1E62) and glycoprotein I by cytotoxic T lymphocytes of either CD4+ or CD8+ phenotype. J Immunol 146: 257–264PubMedGoogle Scholar
  5. 5.
    Baudoux L, Defechereux P, Schoonbroodt S, Merville MP, Rentier B, Piette J (1995) Mutational analysis of varicella-zoster virus major immediate-early protein 1E62. Nucleic Acids Res 23: 1341–1349PubMedCrossRefGoogle Scholar
  6. 6.
    Berger R, Florent G, Just M (1980) Decrease of the lymphoproliferative response to varicella-zoster virus antigen in the aged. Infect Immun 32: 24–27Google Scholar
  7. 7.
    Berger R, Trannoy E, Hollander G, Bailleux F, Rudin C, Creusvaux H (1998) A dose-response study of a live attenuated varicella-zoster virus (Oka strain) vaccine administered to adults 55 years of age and older. J Infect Dis 178 [Suppl] 1: S99–103PubMedCrossRefGoogle Scholar
  8. 8.
    Cabirac GF, Mahalingam R, Wellish M, Gilden DH (1990) Trans-activation of viral tk promoters by proteins encoded by varicella zoster virus open reading frames 61 and 62. Virus Res 15: 57–68PubMedCrossRefGoogle Scholar
  9. 9.
    Cohrs RJ, Barbour M, Gilden DH (1996) Varicella-zoster virus (VZV) transcription during latency in human ganglia: detection of transcripts mapping to genes 21, 29, 62, and 63 in a cDNA library enriched for VZV RNA. J Virol 70: 2789–2796PubMedGoogle Scholar
  10. 10.
    Cohrs RJ, Srock K, Barbour MB, Owens G, Mahalingam R, Devlin ME, Wellish M, Gilden DH (1994) Varicella-zoster virus (VZV) transcription during latency in human ganglia: construction of a cDNA library from latently infected human trigeminal ganglia and detection of a VZV transcript. J Virol 68: 7900–7908PubMedGoogle Scholar
  11. 11.
    Croen KD, Ostrove JM, Dragovic LJ, Straus SE (1988) Patterns of gene expression and sites of latency in human nerve ganglia are different for varicella-zoster and herpes simplex viruses. Proc Natl Acad Sci USA 85: 9773–9777PubMedCrossRefGoogle Scholar
  12. 12.
    Debrus S, Sadzot-Delvaux C, Nikkels AF, Piette J, Rentier B (1995) Varicella-zoster virus gene 63 encodes an immediate-early protein that is abundantly expressed during latency. J Virol 69: 3240–3245PubMedGoogle Scholar
  13. 13.
    Defechereux P, Debrus S, Baudoux L, Rentier B, Piette J (1997) Varicella-zoster virus open reading frame 4 encodes an immediate-early protein with posttranscriptional regulatory properties. J Virol 71: 7073–7079PubMedGoogle Scholar
  14. 14.
    Defechereux P, Debrus S, Baudoux L, Schoonbroodt S, Merville MP, Rentier B, Piette J (1996) Intracellular distribution of the ORF4 gene product of varicella-zoster virus is influenced by the 1E62 protein. J Gen Virol 77: 1505–1513PubMedCrossRefGoogle Scholar
  15. 15.
    Defechereux P, Melen L, Baudoux L, Merville-Louis MP, Rentier B, Piette J (1993) Characterization of the regulatory functions of varicella-zoster virus open reading frame 4 gene product. J Virol 67: 4379–4385PubMedGoogle Scholar
  16. 16.
    Disney GH, McKee TA, Preston CM, Everett RD (1990) The product of varicella-zoster virus gene 62 autoregulates its own promoter. J Gen Virol 71: 2999–3003PubMedCrossRefGoogle Scholar
  17. 17.
    Gilden DH, Rozenman Y, Murray R, Devlin M, Vafai A (1987) Detection of varicellazoster virus nucleic acid in neurons of normal human thoracic ganglia. Ann Neurol 22: 377–380PubMedCrossRefGoogle Scholar
  18. 18.
    Hayward AR, Herberger M (1987) Lymphocyte responses to varicella zoster virus in the elderly. J Clin Immunol 7: 174–178PubMedCrossRefGoogle Scholar
  19. 19.
    Hope-Simpson RE (1965) The nature of herpes zoster: a long-term study and a new hypothesis. Proc R Soc Med 58: 9–20PubMedGoogle Scholar
  20. 20.
    Hyman RW, Ecker JR, Tenser RB (1983) Varicella-zoster virus RNA in human trigeminal ganglia. Lancet 2: 814–816PubMedCrossRefGoogle Scholar
  21. 21.
    Inchauspe G, Nagpal S, Ostrove JM (1989) Mapping of two varicella-zoster virus-encoded genes that activate the expression of viral early and late genes. Virology 173: 700–709PubMedCrossRefGoogle Scholar
  22. 22.
    Jugovic P, Hill AM, Tomazin R, Ploegh H, Johnson DC (1998) Inhibition of major histocompatibility complex class I antigen presentation in pig and primate cells by herpes simplex virus type 1 and 2 ICP47. J Virol 72: 5076–5084PubMedGoogle Scholar
  23. 23.
    Kinchington PR, Bookey D, Turse SE (1995) The transcriptional regulatory proteins encoded by varicella-zoster virus open reading frames (ORFs) 4 and 63, but not ORF 61, are associated with purified virus particles. J Virol 69: 4274–4282PubMedGoogle Scholar
  24. 24.
    Kinchington PR, Hougland JK, Arvin AM, Ruyechan WT, Hay J (1992) The varicellazoster virus immediate-early protein 1E62 is a major component of virus particles. J Virol 66: 359–366PubMedGoogle Scholar
  25. 25.
    Levin MJ, Barber D, Goldblatt E, Jones M, LaFleur B, Chan C, Stinson D, Zerbe GO, Hayward AR (1998) Use of a live attenuated varicella vaccine to boost varicella-specific immune responses in seropositive people 55 years of age and older: duration of booster effect. J Infect Dis 178 [Suppl 1]: S109—S112PubMedCrossRefGoogle Scholar
  26. 26.
    Lungu O, Annunziato PW, Gershon A, Staugaitis SM, Josefson d, Larussa P, Silverstein SJ (1995) Reactivated and latent varicella-zoster virus in human dorsal root ganglia. Proc Natl Acad Sci USA 92: 10980–10984PubMedCrossRefGoogle Scholar
  27. 27.
    Lungu O, Annunziato PW (1999) Varicella-zoster virus: latency and reactivation. In: Wolff MH, Schiinemann S, Schmidt A (eds) Varicella-zoster virus. Molecular biology, pathogenesis and clinical aspects. Karger, Basel, pp 61–75CrossRefGoogle Scholar
  28. 28.
    Lungu O, Panagiotidis CA, Annunziato PW, Gershon AA, Silverstein SJ (1998) Aberrant intracellular localization of varicella-zoster virus regulatory proteins during latency. Proc Natl Acad Sci USA 95: 7080–7085PubMedCrossRefGoogle Scholar
  29. 29.
    Mahalingam R, Kennedy PGE, Gilden DH (1999) The problems of latent varicella eoster virus in human ganglia:precise cell location and viral content. J Neurovirol 5: 445–446PubMedCrossRefGoogle Scholar
  30. 30.
    Mahalingam R, Wellish M, Cohrs R, Debrus S, Piette J, Rentier B, Gilden DH (1996) Expression of protein encoded by varicella-zoster virus open reading frame 63 in latently infected human ganglionic neurons. Proc Natl Acad Sci USA 93: 2122–2124PubMedCrossRefGoogle Scholar
  31. 31.
    Meier JL, Holman RP, Croen KD, Smialek JE, Straus SE (1993) Varicella-zoster virus transcription in human trigeminal ganglia. Virology 193: 193–200PubMedCrossRefGoogle Scholar
  32. 32.
    Moriuchi H, Moriuchi M, Straus SE, Cohen JI (1993) Varicella-zoster virus (VZV) open reading frame 61 protein transactivates VZV gene promoters and enhances the infectivity of VZV DNA. J Virol 67: 4290–4295PubMedGoogle Scholar
  33. 33.
    Nagpal S, Ostrove JM (1991) Characterization of a potent varicella-zoster virus-encoded trans-repressor. J Virol 65: 5289–5296PubMedGoogle Scholar
  34. 34.
    Nikkels AF, Debrus S, Sadzot-Delvaux C, Piette J, Rentier B, Pierard GE (1995) Immunohistochemical identification of varicella-zoster virus gene 63-encoded protein (1E63) and late (gE) protein on smears and cutaneous biopsies: implications for diagnostic use. J Med Virol 47: 342–347PubMedCrossRefGoogle Scholar
  35. 35.
    Patel Y, Gough G, Coffin RS, Thomas S, Cohen JI, Latchman DS (1998) Cell type specific repression of the varicella zoster virus immediate early gene 62 promoter by the cellular Oct-2 transcription factor. Biochim Biophys Acta 1397: 268–274PubMedCrossRefGoogle Scholar
  36. 36.
    Pereira RA, Tscharke DC, Simmons A (1994) Upregulation of class I major histocompatibility complex gene expression in primary sensory neurons, satellite cells, and Schwann cells of mice in response to acute but not latent herpes simplex virus infection in vivo. J Exp Med 180: 841–850PubMedCrossRefGoogle Scholar
  37. 37.
    Perera LP, Kaushal S, Kinchington PR, Mosca JD, Hayward GS, Straus SE (1994) Varicella-zoster virus open reading frame 4 encodes a transcriptional activator that is functionally distinct from that of herpes simplex virus homology ICP27. J Virol 68: 2468–2477PubMedGoogle Scholar
  38. 38.
    Perera LP, Mosca JD, Sadeghi-Zadeh M, Ruyechan WT, Hay J (1992) The varicellazoster virus immediate early protein, 1E62, can positively regulate its cognate promoter. Virology 191: 346–354PubMedCrossRefGoogle Scholar
  39. 39.
    Sadzot-Delvaux C, Debrus S, Nikkels A, Piette J, Rentier B (1995) Varicella-zoster virus latency in the adult rat is a useful model for human latent infection. Neurology 45: S18—S20PubMedCrossRefGoogle Scholar
  40. 40.
    Sadzot-Delvaux C, Kinchington PR, Debrus S, Rentier B, Arvin AM (1997) Recognition of the latency-associated immediate early protein 1E63 of varicella-zoster virus by human memory T lymphocytes. J Immunol 159: 2802–2806PubMedGoogle Scholar
  41. 41.
    Shiraki K, Hyman RW (1987) The immediate early proteins of varicella-zoster virus. Virology 156: 423–426PubMedCrossRefGoogle Scholar
  42. 42.
    Tomazin R, Hill AB, Jugovic P, York I, van Endert P, Ploegh HL, Andrews DW, Johnson DC (1996) Stable binding of the herpes simplex virus ICP47 protein to the peptide binding site of TAP. EMBO J 15: 3256–3266PubMedGoogle Scholar
  43. 43.
    Vafai A, Murray RS, Wellish M, Devlin M, Gilden DH (1988) Expression of varicellazoster virus and herpes simplex virus in normal human trigeminal ganglia. Proc Nail Acad Sci USA 85: 2362–2366CrossRefGoogle Scholar
  44. 44.
    Whitley RJ (1996) Herpes simplex virus. In: Fields BN, Knipe DM, Howley PM (eds) Virology. Lippincott-Raven, New York, pp 2297–2342Google Scholar
  45. 45.
    Wroblewska Z, Valyi-Nagy T, Otte J, Dillner A, Jackson A, Sole DP, Fraser NW (1993) A mouse model for varicella-zoster virus latency. Microb Pathog 15: 141–151PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2001

Authors and Affiliations

  • C. Sadzot-Delvaux
    • 1
    • 2
  • B. Rentier
    • 1
  1. 1.Department of Microbiology, Fundamental VirologyLiège UniversityBelgium
  2. 2.Department of Microbiology, Fundamental Virology, Pathology B23Liège UniversityBelgium

Personalised recommendations