The human tumour virus Epstein–Barr virus (EBV) encodes a 17 kDa protein, BHRF1, which is a member of the -2 family and has been shown to suppress apoptosis. The role of this gene in the life-cycle of EBV has not been fully elucidated. In order to identify motifs conserved in herpesviruses and possibly shed light on its function we isolated a BHRF1 homologue from herpesvirus papio (cercopithecine herpesvirus12) a closely related gammaherpesvirus of baboons. The gene, hvpBHRF1, also encodes a 17 kDa protein which shares 64% identity and 79% similarity with EBV BHRF1 at the amino acid level. In biological assays, hvpBHRF1 and BHRF1 conferred similar levels of protection on human keratinocytes induced to apoptose with -platin.


Article metrics loading...

Loading full text...

Full text loading...



  1. Austin, P. J., Flemington, E., Yandava, C. N., Strominger, J. L. & Speck, S. H. (1988). Complex transcription of the Epstein–Barr virus BamHI fragment H rightward open reading frame 1 (BHRF1) in latently and lytically infected B lymphocytes.Proceedings of the National Academy of Sciences, USA 85, 3678-3682.[CrossRef] [Google Scholar]
  2. Cheng, E. H., Nicholas, J., Bellows, D. S., Hayward, G. S., Guo, H. G., Reitz, M. S. & Hardwick, J. M. (1997). A Bcl-2 homolog encoded by Kaposi sarcoma-associated virus, human herpesvirus 8, inhibits apoptosis but does not heterodimerize with Bax or Bak.Proceedings of the National Academy of Sciences, USA 94, 690-694.[CrossRef] [Google Scholar]
  3. Cleary, M. L., Smith, S. D. & Sklar, J. (1986). Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation.Cell 47, 19-28.[CrossRef] [Google Scholar]
  4. Dawson, C. W., Eliopoulos, A. G., Dawson, J. & Young, L. S. (1995). BHRF1, a viral homologue of the Bcl-2 oncogene, disturbs epithelial cell differentiation.Oncogene 10, 69-77. [Google Scholar]
  5. Dawson, C. W., Dawson, J., Jones, R., Ward, K. & Young, L. S. (1998). Functional differences between BHRF1, the Epstein-Barr virus-encoded Bcl-2 homologue, and Bcl-2 in human epithelial cells.Journal of Virology 72, 9016-9024. [Google Scholar]
  6. Eliopoulos, A. G., Dawson, C. W., Mosialos, G., Floettmann, J. E., Rowe, M., Armitage, R. J., Dawson, J., Zapata, J. M., Kerr, D. J., Wakelam, M. J., Reed, J. C., Kieff, E. & Young, L. S. (1996). CD40-induced growth inhibition in epithelial cells is mimicked by Epstein–Barr virus-encoded LMP1: involvement of TRAF3 as a common mediator.Oncogene 13, 2243-2254. [Google Scholar]
  7. Falk, L. A., Henle, G., Henle, W., Deinhardt, F. & Schudel, A. (1977). Transformation of lymphocytes by Herpesvirus papio.International Journal of Cancer 20, 219-226.[CrossRef] [Google Scholar]
  8. Fanidi, A., Hancock, D. C. & Littlewood, T. D. (1998). Suppression of c-Myc-induced apoptosis by the Epstein–Barr virus gene product BHRF1.Journal of Virology 72, 8392-8395. [Google Scholar]
  9. Foghsgaard, L. & Jaattela, M. (1997). The ability of BHRF1 to inhibit apoptosis is dependent on stimulus and cell type.Journal of Virology 71, 7509-7517. [Google Scholar]
  10. Franken, M., Annis, B., Ali, A. N. & Wang, F. (1995). 5′ coding and regulatory region sequence divergence with conserved function of the Epstein–Barr virus LMP2A homolog in herpesvirus papio.Journal of Virology 69, 8011-8019. [Google Scholar]
  11. Franken, M., Devergne, O., Rosenzweig, M., Annis, B., Kieff, E. & Wang, F. (1996). Comparative analysis identifies conserved tumor necrosis factor receptor-associated factor 3 binding sites in the human and simian Epstein–Barr virus oncogene LMP1.Journal of Virology 70, 7819-7826. [Google Scholar]
  12. Fuentes-Panana, E. M., Swaminathan, S. & Ling, P. D. (1999). Transcriptional activation signals found in the Epstein–Barr virus (EBV) latency C promoter are conserved in the latency C promoter sequences from baboon and rhesus monkey EBV-like lymphocryptoviruses (cercopithicine herpesviruses 12 and 15).Journal of Virology 73, 826-833. [Google Scholar]
  13. Heller, M. & Kieff, E. (1981). Colinearity between the DNAs of Epstein–Barr virus and herpesvirus papio.Journal of Virology 37, 821-826. [Google Scholar]
  14. Heller, M., Gerber, P. & Kieff, E. (1981). Herpesvirus papio DNA is similar in organization to Epstein–Barr virus DNA.Journal of Virology 37, 698-709. [Google Scholar]
  15. Henderson, S., Huen, D., Rowe, M., Dawson, C., Johnson, G. & Rickinson, A. (1993). Epstein–Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death.Proceedings of the National Academy of Sciences, USA 90, 8479-8483.[CrossRef] [Google Scholar]
  16. Hickish, T., Robertson, D., Clarke, P., Hill, M., di Stefano, F., Clarke, C. & Cunningham, D. (1994). Ultrastructural localization of BHRF1: an Epstein–Barr virus gene product which has homology with bcl-2.Cancer Research 54, 2808-2811. [Google Scholar]
  17. Hockenbery, D. M., Oltvai, Z. N., Yin, X. M., Milliman, C. L. & Korsmeyer, S. J. (1993). Bcl-2 functions in an antioxidant pathway to prevent apoptosis.Cell 75, 241-251.[CrossRef] [Google Scholar]
  18. Jenson, H. B., Ench, Y., Gao, S.-J., Rice, K., Carey, D., Kennedy, R. C., Arrand, J. A. & Mackett, M. (2000). Epidemiology of herpesvirus papio in a large captive baboon colony: similarities to Epstein–Barr virus infection in humans.Journal of Infectious Diseases 181, 1462-1466.[CrossRef] [Google Scholar]
  19. Kawanishi, M. (1997). Epstein–Barr virus BHRF1 protein protects intestine 407 epithelial cells from apoptosis induced by tumor necrosis factor alpha and anti-Fas antibody.Journal of Virology 71, 3319-3322. [Google Scholar]
  20. Khanim, F., Dawson, C., Meseda, C. A., Dawson, J., Mackett, M. & Young, L. S. (1997). BHRF1, a viral homologue of the Bcl-2 oncogene, is conserved at both the sequence and functional level in different Epstein–Barr virus isolates.Journal of General Virology 78, 2987-2999. [Google Scholar]
  21. Kieff, E. & Shenk, T. (1998). Modulation of apoptosis by herpesviruses.Seminars in Virology 8, 471-480.[CrossRef] [Google Scholar]
  22. Kozak, M. (1986). Point mutations define a sequence flanking the AUG initiation codon that modulates translation by eukaryotic ribosomes.Cell 44, 283-292.[CrossRef] [Google Scholar]
  23. Lee, M. A. & Yates, J. L. (1992). BHRF1 of Epstein–Barr virus, which is homologous to human proto-oncogene bcl2, is not essential for transformation of B cells or for virus replication in vitro.Journal of Virology 66, 1899-1906. [Google Scholar]
  24. Ling, P. D., Ryon, J. J. & Hayward, S. D. (1993). EBNA-2 of herpesvirus papio diverges significantly from the type A and type B EBNA-2 proteins of Epstein–Barr virus but retains an efficient transactivation domain with a conserved hydrophobic motif.Journal of Virology 67, 2990-3003. [Google Scholar]
  25. Loeb, D. D., Sung, N. S., Pesano, R. L., Sexton, C. J., Hutchison, C. D. & Pagano, J. S. (1990). Plasmid origin of replication of herpesvirus papio: DNA sequence and enhancer function.Journal of Virology 64, 2876-2883. [Google Scholar]
  26. Lowe, S. W., Ruley, H. E., Jacks, T. & Housman, D. E. (1993). p53-dependent apoptosis modulates the cytotoxicity of anticancer agents.Cell 74, 957-967.[CrossRef] [Google Scholar]
  27. Marchini, A., Tomkinson, B., Cohen, J. I. & Kieff, E. (1991). BHRF1, the Epstein–Barr virus gene with homology to Bc12, is dispensable for B-lymphocyte transformation and virus replication.Journal of Virology 65, 5991-6000. [Google Scholar]
  28. Marshall, W. J., Yim, C., Gustafson, E., Graf, T., Sage, D. R., Hanify, K., Williams, L., Fingeroth, J. & Finberg, R. W. (1999). Epstein–Barr virus encodes a novel homolog of the bcl-2 oncogene that inhibits apoptosis and associated with Bax and Bak.Journal of Virology 73, 5181-5185. [Google Scholar]
  29. Meseda, C. A. (1999).Functional analysis of BHRF1, the Bcl-2 homologue of Epstein–Barr virus. PhD thesis. University of Manchester, UK.
  30. Moghaddam, A., Koch, J., Annis, B. & Wang, F. (1998). Infection of human B lymphocytes with lymphocryptoviruses related to Epstein–Barr virus.Journal of Virology 72, 3205-3212. [Google Scholar]
  31. Nava, V. E., Cheng, E. H., Veliuona, M., Zou, S., Clem, R. J., Mayer, M. L. & Hardwick, J. M. (1997). Herpesvirus saimiri encodes a functional homolog of the human bcl-2 oncogene.Journal of Virology 71, 4118-4122. [Google Scholar]
  32. Pearson, G. R., Luka, J., Petti, L., Sample, J., Birkenbach, M., Braun, D. & Kieff, E. (1987). Identification of an Epstein–Barr virus early gene encoding a second component of the restricted early antigen complex.Virology 160, 151-161.[CrossRef] [Google Scholar]
  33. Ryon, J. J., Fixman, E. D., Houchens, C., Zong, J., Lieberman, P. M., Chang, Y. N., Hayward, G. S. & Hayward, S. D. (1993). The lytic origin of herpesvirus papio is highly homologous to Epstein-Barr virus ori-Lyt: evolutionary conservation of transcriptional activation and replication signals.Journal of Virology 67, 4006-4016. [Google Scholar]
  34. Sarid, R., Sato, T., Bohenzky, R. A., Russo, J. J. & Chang, Y. (1997). Kaposi’s sarcoma-associated herpesvirus encodes a functional bcl-2 homologue.Nature Medicine 3, 293-298.[CrossRef] [Google Scholar]
  35. Shen, Y. & Shenk, T. E. (1995). Viruses and apoptosis.Current Opinion in Genetics and Development 5, 105-111.[CrossRef] [Google Scholar]
  36. Sorenson, C. M., Barry, M. A. & Eastman, A. (1990). Analysis of events associated with cell cycle arrest at G2 phase and cell death induced by cisplatin.Journal of the National Cancer Institute 82, 749-755.[CrossRef] [Google Scholar]
  37. Teodoro, J. G. & Branton, P. E. (1997). Regulation of apoptosis by viral gene products.Journal of Virology 71, 1739-1746. [Google Scholar]
  38. Theodorakis, P., D’Sa-Eipper, C., Subramanian, T. & Chinnadurai, G. (1996). Unmasking of a proliferation-restraining activity of the anti-apoptosis protein EBV BHRF1.Oncogene 12, 1707-1713. [Google Scholar]
  39. Toczyski, D. P. & Steitz, J. A. (1993). The cellular RNA-binding protein EAP recognizes a conserved stem–loop in the Epstein-Barr virus small RNA EBER 1.Molecular and Cellular Biology 13, 703-710. [Google Scholar]
  40. Tsujimoto, Y., Finger, L. R., Yunis, J., Nowell, P. C. & Croce, C. M. (1984). Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation.Science 226, 1097-1099.[CrossRef] [Google Scholar]
  41. Vaux, D. L., Cory, S. & Adams, J. M. (1988). Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells.Nature 335, 440-442.[CrossRef] [Google Scholar]
  42. Yates, J. L., Camiolo, S. M., Ali, S. & Ying, A. (1996). Comparison of the EBNA1 proteins of Epstein–Barr virus and herpesvirus papio in sequence and function.Virology 222, 1-13.[CrossRef] [Google Scholar]
  43. Young, L. S., Dawson, C. W. & Eliopoulos, A. G. (1997). Viruses and apoptosis.British Medical Bulletin 53, 509-521.[CrossRef] [Google Scholar]

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error