Skip to main content
SpringerLink
Log in

The Epstein-Barr virus latency and reactivation

  • Chapter
Cancer in Transplantation: Prevention and Treatment

Part of the book series: Transplantation and Clinical Immunology ((TRAC,volume 27))

  • 60 Accesses

Abstract

The Epstein—Barr virus (EBV) is a widely-spread human herpes virus, that persists latently for the life time of the infected host. The life-long exposure to EBV and the fact that EBV-infected B lymphocytes from the peripheral blood have the potential to proliferate continuously (immortalization), are believed to be predisposing factors for the emergence of EBV-associated human malignancies like Burkitt’s Lymphoma (BL), Nasopharyngeal Carcinoma (NPC), Hodgkin’s disease (HD), and B and T cell lymphomas in immunocompromised individuals [1]. Little is known about the EBV persistence in vivo, and the only models for EBV latency and reactivation are B-cells immortalised in vitro or Burkitt lymphomas cell lines. In such cells, only a minority of the viral genes are expressed and define latency. In this chapter, the molecular mechanisms of EBV-mediated immortalisation of B cells, latency and reactivation will be shortly presented.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Kieff E, Liebowitz D. Epstein-Barr virus and its replication. In: Fields B N, Knipe D M, Chanock R M, Hirsch M S, Melnick J L, Monath T P, Roizman B, editors, Virology, 2nd ed., New York: Raven Press, 1990: 1889–1920.

    Google Scholar 

  2. Hammerschmidt W, Sugden B. Genetic analysis of functions of Epstein-Barr virus in human B lymphocytes. Nature 1989; 340: 393–397.

    Article  PubMed  CAS  Google Scholar 

  3. Cohen J F, Wang F, Mannick J, Kieff E. Epstein-Barr virus nuclear protein 2is a key determinant of lymphocyte transformation. Proc Natl Acad Sci USA 1989; 86: 9558–9562.

    Article  PubMed  CAS  Google Scholar 

  4. Mannick J B, Cohen J I, Birkenbach M, Marchini A, Kieff E. The Epstein-Barr virus nuclear protein encoded by the leader of the EBNA RNAs is important in B cell transformation. J Virol 1991; 65: 6826–6837.

    PubMed  CAS  Google Scholar 

  5. Kaye K, Izumi K M, Kieff E. Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc Natl Acad Sci USA 1993; 90: 9150–9154.

    Article  PubMed  CAS  Google Scholar 

  6. Tomkinson B, Robertson E, Kieff E. Epstein-Barr virus nuclear proteins EBNA3A and EBNA3C are essential for B lymphocyte growth transformation. J Virol 1993; 67: 2014–2025.

    PubMed  CAS  Google Scholar 

  7. Yates J, Warren N, Reisman D, Sugden B. A cis acting element from the Epstein-Barr virus genome that permits stable replication of recombinant plasmids in latently infected cells. Proc Natl Acad Sci USA 1984; 81: 3806–3810.

    Article  PubMed  CAS  Google Scholar 

  8. Calender A, Billaud M, Aubry J-P, Banchereau J, Vuillaume M, Lenoir G M. Epstein- Barr virus induces expression of B cell activation markers on in vitro infection of EBV negative lymphoma cells. Proc Natl Acad Sci USA 1987; 84: 8060–8064.

    Article  PubMed  CAS  Google Scholar 

  9. Cordier M, Calender A, Billaud M, Zimber U, Rousselet G, Pavlish O, Banchereau J, Tursz T, Bornkamm G, Lenoir G M. Stable transfection of EBV nuclear antigen 2 in lymphoma cells containing the EBV P3HR1 genome induces expression of B-cell activation molecules. J Virol 1990; 64: 1002–1013.

    PubMed  CAS  Google Scholar 

  10. Wang F, Gregory C D, Rowe M, Rickinson A B, Wang D, Birkenbach M, Kikutani H, Kishimoto T, Kieff E. Epstein-Barr virus nuclear protein 2 specifically induces expression of the B cell antigen CD23. Proc Natl Acad Sci USA 1987; 84: 3452–3456.

    Article  PubMed  CAS  Google Scholar 

  11. Knuston J C. The level of c-fgr RNA is increased by EBNA2, an EBV gene required for B-cell immortalisation. J Virol 1990; 64: 2530–2536.

    Google Scholar 

  12. Abbot S D, Rowe M, Cadwallader K, Ricksten A, Gordon J, Wang F, Rymo L, Rickinson A B. Epstein-Barr virus 2 induces expression of the virus-encoded latent membrane protein. J Virol 1990; 64: 2126–2134.

    PubMed  CAS  Google Scholar 

  13. Fahraeus R, Jansson A, Ricksten A, Sjöblom A, Rymo L. Epstein-Barr virus nuclear antigen 2 activates the latent membrane protein promoter by modulating the activity of a negative regulatory element. Proc Natl Acad Sci USA 1990; 87: 7390–7394.

    Article  PubMed  CAS  Google Scholar 

  14. Zimber-Strobl U, Suentzenich K-O, Laux G, Eick D, Cordier M, Calender A, Billaud M, Lenoir G M, Bornkamm G W. Epstein-Barr virus nuclear antigen 2 activates transcription of the terminal protein gene. J Virol 1991; 65: 415–423.

    PubMed  CAS  Google Scholar 

  15. Sung N S, Kenney S, Gutsch D, Pagano J S. EBNA2 transactivates a lymphoid-specific enhancer in the BamHI C promoter of Epstein-Barr virus. J Virol 1991; 65: 2164–2169.

    PubMed  CAS  Google Scholar 

  16. Rooney C M, Brimmell M, Buschle M, Allan G, Farrell P J, Kolman J L. Host cell and EBNA2 regulation of EBV latent cycle promoter activity in B lymphocytes. J Virol 1992; 66: 496–504.

    PubMed  CAS  Google Scholar 

  17. Tsang S-F, Wang F, Izumi K M, Kieff E. Delineation of the cis-acting element mediating EBNA2 transactivation from latent infection membrane protein expression. J Virol 1991; 65: 6765–6771.

    PubMed  CAS  Google Scholar 

  18. Wang F, Kikutani H, Tsang S-F, Kishimoto T, Kieff E. Epstein-Barr virus nuclear antigen 2 transactivates a cis-acting CD23 DNA element. J Virol 1991; 65: 4101–4106.

    PubMed  CAS  Google Scholar 

  19. Jin X W, Speck S. Identification of critical cis elements involved in mediating Epstein- Barr virus nuclear antigen 2-dependent activity of an enhancer located upstream of the viral BamHI C promoter. J Virol 1992; 66: 2846–2852.

    PubMed  CAS  Google Scholar 

  20. Ling P D, Rawlins D R, Hayward S D. The Epstein-Barr virus immortalising protein EBNA2 is targeted to DNA by cellular enhance binding protein. Proc Natl Acad Sci USA 1993; 90: 9237–9241.

    Article  PubMed  CAS  Google Scholar 

  21. Zimber-Strobl U, Kremmer E, Grässer F, Marschall G, Laux G, Bornkamm G W. The Epstein-Barr virus nuclear antigen 2 interacts with an EBNA2-responsive cis-element of the terminal protein 1 gene promoter. EMBO J 1993; 12: 167–175.

    PubMed  CAS  Google Scholar 

  22. Tun T, Hamaguchi Y, Matsunami N, Furukawa T, Honjo T, Kawaichi M. Recognition sequence of a highly conserved DNA binding protein RBP-J kappa. Nucleic Acids Res 1994; 22: 965–971.

    Article  PubMed  CAS  Google Scholar 

  23. Israel, A, Yano, O, Logeat, F, Kieran, M. and Kourilsky, P. Nucleic Acids Res 1989; 17, 5245–5257.

    Article  PubMed  CAS  Google Scholar 

  24. Grossman S R, Johannsen E, Tong X, Yalamanchini R, Kieff E. The EBV nuclear antigen 2 transactivator is directed to response elements by the Jk recombination signal binding protein. Proc Natl Acad Sci USA 1994; 91: 7568–7572.

    Article  PubMed  CAS  Google Scholar 

  25. Henkel T, Ling P D, Hayward S D, Peterson M G. Mediation of EBV EBNA2 transactivation by recombination signal binding protein Jk. Science 1994; 26: 92–95.

    Article  Google Scholar 

  26. Zimber-Strobl U, Strobl L, Meitinger C, Hinrichs R, Sakai T, Honjo T, Bornkamm G. EBV nuclear antigen 2 exerts its transactivating function through interaction with recombination signal binding protein RBP-Jk, the homologue of Drosophila suppressor of Hairless. EMBO J 1994; 13: 4973–4982.

    PubMed  CAS  Google Scholar 

  27. Waltzer L, Logeat F, Brou C, Israel A, Sergeant A, Manet E. The human Jk recombination signal sequence binding protein (RBP-JK) targets the Epstein-Barr virus EBNA2 protein to its DNA responsive elements. EMBO J 1994; 13: 5633–5638.

    PubMed  CAS  Google Scholar 

  28. Hsieh JJ-D, Hayward SD. Masking of the CBF1/RBP-JK transcriptional repression domain by EBV EBNA2. Science 1995; 268:560–563.

    Article  PubMed  CAS  Google Scholar 

  29. Furukawa T, Kawaichi M, Matsunami N, Ryo H, Nishida Y, Honjo T. The drosophila RBP-J kappa gene encodes the binding protein for the immunoglobulin Jk recombination signal sequence. J Biol Chem 1991; 266: 23334–23340.

    PubMed  CAS  Google Scholar 

  30. Schweisguth F, Posakony J W. Suppressor of Hairless, the drosophila homolog of the mouse recombination signal-binding protein gene, controls sensory organ cell fate. Cell 1992; 69: 1199–1212.

    Article  PubMed  CAS  Google Scholar 

  31. Fortini ME, Artavanis-Tsakonas S. The suppressor of Hairless protein participates in Notch receptor signalling. Cell 1994; 79: 273–282.

    Article  PubMed  CAS  Google Scholar 

  32. Ellisen LW, Bird J, West D, Soreng AL, Reynolds TC, Smith S, Sklar J. TAN-1, the human homolog of the drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 1991; 66: 649–661.

    Article  PubMed  CAS  Google Scholar 

  33. Le Roux A, Kerdiles B, Walls D, Dedieu JF, Perricaudet M. The EBV determined nuclear antigens EBNA3A, B and C repress EBNA2 mediated transactivation of the viral TP1 gene promoter. Virol 1994; 205: 596–602.

    Article  Google Scholar 

  34. Robertson ES, Grossman S, Johannsen E, Miller C, Lin J, Tomkinson B, Kieff E. Epstein-Barr virus nuclear protein 3C modulates transcription through interaction with the sequence specific DNA-binding protein Jk. J Virol 1995; 69: 3108–3116.

    PubMed  CAS  Google Scholar 

  35. Sinclair A, Palmero I, Peters G, Farrell P. EBNA2 and EBNA-LP cooperate to cause GO to G1 transition during immortalisation of resting human B lymphocytes by EBV. EMBO J 1994; 13: 3321–3328.

    PubMed  CAS  Google Scholar 

  36. Wang D, Liebowitz D, Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell 1985; 43: 831–840.

    Article  PubMed  CAS  Google Scholar 

  37. Wang D, Liebowitz D, Wang F, Gregory C, Rickinson A, Larson R, Springer T, Kieff E. Epstein-Barr virus latent infection membrane protein alters the human B-lymphocyte phenotype: deletion of the amino-terminus abolishes activity. J Virol 1988b; 62: 4173–4184.

    PubMed  CAS  Google Scholar 

  38. Peng M, Lundgren E. Transient expression of the Epstein-Barr virus LMP1 gene in B-cell chronic lymphocytic leukaemia cells, T cells, and hematopoietic cell lines: cell- type-independent-induction of CD23, CD21 and ICAM-1. Leukemia 1993; 7: 104–112.

    PubMed  CAS  Google Scholar 

  39. Hamarskjold M L, Simurda M C. Epstein-Barr virus latent membrane protein transactivates the human immunodeficiency virus type 1 long terminal repeat through induction of NF-KB activity. J Virol 1992; 66: 6496–6501.

    Google Scholar 

  40. Rowe M, Peng-Pilon M, Huen D S, Hardy R, Croom-Carter D, Lundgren E, Rickinson A B. Up regulation of Bcl-2 by the Epstein-Barr virus latent membrane protein LMP1: a B-cell specific response that is delayed relative to NF-kB activation and to induction of cell surface markers. J Virol 1994; 68: 5602–5612.

    PubMed  CAS  Google Scholar 

  41. Liou H C, Baltimore D. Regulation of the NF-kB/rel transcription factor and IkB inhibitor system. Curr Opin Cell Biol 1993; 5: 477–487.

    Article  PubMed  CAS  Google Scholar 

  42. Mosialos G, Birkenbach M, Yalamanchili R, VanArsdale T, Ware C, Kieff E. The Epstein- Barr virus transforming protein LMP1 engages signalling proteins for the tumor necrosis factor receptor family. Cell 1995; 80: 389–399.

    Article  PubMed  CAS  Google Scholar 

  43. Mitchell T, Sugden B. Stimulation of NF-kB-mediated transcription by mutant derivates of the latent membrane protein of Epstein-Barr virus. J Virol 1995; 69: 2968–2976.

    PubMed  CAS  Google Scholar 

  44. Rowe M, Rowe D T, Gregory C D, Young L S, Farrell P J, Rupani H, Rickinson A B. Differences in B-cell growth phenotype reflect novel patterns of Epstein-Barr virus latent gene expression in Burkitt’s lymphoma cells. EMBO J 1987; 6: 2743–2751.

    PubMed  CAS  Google Scholar 

  45. Countryman J, Miller G. Activation of expression of latent Epstein-Barr herpesvirus after gene transfer with a small cloned fragment of heterogeneous viral DNA. Proc Natl Acad Sci USA 1985; 82: 4085–4089.

    Article  PubMed  CAS  Google Scholar 

  46. Chevallier-Greco A, Manet E, Chavrier P, Mosnier C, Daillie J, Sergeant A. Both Epstein- Barr virus encoded trans-acting factors, EB1 and EB2, are required to activate transcription from an EBV early promoter. EMBO J 1986; 5: 3243–3249.

    PubMed  CAS  Google Scholar 

  47. Hardwick J M, Lieberman P, Hayward S D. A new Epstein-Barr virus transactivator R, induces expression of a cytoplasmic early antigen. J Virol 1988; 62: 2274–2284.

    PubMed  CAS  Google Scholar 

  48. Farrell P J, Rowe D T, Rooney C M, Kouzarides T. Epstein-Barr virus BZLF1 transactivator specifically binds to a consensus AP-1 site and is related to c-fos. EMBO J 1989; 8: 127–132.

    PubMed  CAS  Google Scholar 

  49. Urier G, Buisson M, Chambard P, A. Sergeant. The Epstein-Barr early protein EB1 activates transcription from different responsive elements including AP-1 binding sites. EMBO J 1989; 8: 1447–1453.

    PubMed  CAS  Google Scholar 

  50. Lieberman P, Berk A J. In vitro transcriptional activation, dimerisation, and DNA-binding specificity of the Epstein-Barr virus Zta protein. J Virol 1990; 64: 2560–2568.

    PubMed  CAS  Google Scholar 

  51. Kouzarides T, Packham G, Cook A, Farrell P J. The BZLF1 protein of EBV has a coiled coil dimerisation domain without a heptad leucine repeat but with homology to the CEB/P leucine zipper. Oncogene 1991; 6: 195–204.

    PubMed  CAS  Google Scholar 

  52. Hammerschmidt W, Sugden B. Identification and characterisation of orilyt, a lytic origin of DNA replication of Epstein-Barr virus. Cell 1988; 55: 427–433.

    Article  PubMed  CAS  Google Scholar 

  53. Gruffat H, Manet E, Rigolet A, A.Sergeant. The EBV enhancer factor R is a sequence- specific DNA-binding protein. Nucleic Acids Res 1990; 18: 6835–6843.

    Article  PubMed  CAS  Google Scholar 

  54. Gruffat H, A. Sergeant. Characterisation of the DNA-binding site repertoire for the EBV transcription factor R. Nucleic Acids Res 1994; 22: 1172–1178.

    Article  PubMed  CAS  Google Scholar 

  55. Manet E, Gruffat H, Trescol-Biemont M C, Moreno N, Chambard P, Giot J F, Sergeant A. Epstein-Barr Virus bicistronic mRNAs generated by facultative splicing code for two transcriptional activators. EMBO J 1989; 8: 1819–1826.

    PubMed  CAS  Google Scholar 

  56. Flemington E, Goldfeld A E, Speck S. Efficient transcription of the Epstein-Barr virus immediate-early BZLF1 and BRLF1 genes requires protein synthesis. J Virol 1991; 65: 7073–7077.

    PubMed  CAS  Google Scholar 

  57. Flemington E, Speck S H. Autoregulation of Epstein-Barr virus BZLF1 putative lytic switch gene. J Virol 1990; 64: 1227–1232.

    PubMed  CAS  Google Scholar 

  58. Sinclair A J, Brimmel M, Shanahan F, Farrell P J. Pathways of activation of the Epstein-Barr virus productive cycle. J Virol 1991; 65: 2237–2244.

    PubMed  CAS  Google Scholar 

Download references

Authors
  1. Alain Sergeant
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Hôpital Edouard Herriot, Pavillon P, 5, Place d’Arsonval, 69437, Lyon 3, France

    J. L. Touraine

Rights and permissions

Reprints and permissions

Copyright information

© 1996 Kluwer Academic Publishers

About this chapter

Cite this chapter

Sergeant, A. (1996). The Epstein-Barr virus latency and reactivation. In: Touraine, J.L., Traeger, J., Bétuel, H., Dubernard, J.M., Revillard, J.P., Dupuy, C. (eds) Cancer in Transplantation: Prevention and Treatment. Transplantation and Clinical Immunology, vol 27. Springer, Dordrecht. https://doi.org/10.1007/978-94-009-0175-9_21

Download citation

  • DOI: https://doi.org/10.1007/978-94-009-0175-9_21

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-94-010-6563-4

  • Online ISBN: 978-94-009-0175-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation