1887

Abstract

Chronic active Epstein–Barr virus infection (CAEBV) has been considered to be a non-neoplastic T-cell lymphoproliferative disease associated with Epstein–Barr virus (EBV) infection. In EBV-associated diseases, the cell phenotype-dependent differences in EBV latent gene expression may reflect the strategy of the virus in relation to latent infection. We previously reported that EBV latent gene expression was restricted; EBV nuclear antigen 1 (EBNA1) transcripts were consistently detected in all spleen samples from five CAEBV patients, but EBNA2 transcripts were detected in only one sample. EBV latent gene expression is controlled by distinct usage of three EBNA promoters (Cp, Wp and Qp). In this study, we examined the EBNA promoter usage by RT-PCR and the methylation status in the Cp and Wp regions using bisulfite PCR analysis in spleen samples from CAEBV patients. EBNA1 transcripts were unexpectedly initiated not from Qp but from Cp in all samples in spite of the restricted form of latency. Furthermore, while Cp was active, Cp was heavily methylated, indicating that CAEBV has unique EBV latent gene expression, EBNA promoter usage and EBNA promoter methylation status, in part due to unique splicing of Cp-initiated transcripts and an activation mechanism in hypermethylated Cp.

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2003-05-01
2024-03-28
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References

  1. Alfieri C., Birkenbach M., Kieff E. 1991; Early events in Epstein–Barr virus infection of human B lymphocytes. Virology 181:595–608
    [Google Scholar]
  2. Baer R., Bankier A. T., Biggin M. D. 9 other authors 1984; DNA sequence and expression of the B95-8 Epstein–Barr virus genome. Nature 310:207–211
    [Google Scholar]
  3. Bell A., Skinner J., Kirby H., Rickinson A. 1998; Characterisation of regulatory sequences at the Epstein–Barr virus Bam HI W promoter. Virology 252:149–161
    [Google Scholar]
  4. Bodescot M., Perricaudet M. 1986; Epstein–Barr virus mRNAs produced by alternative splicing. Nucleic Acids Res 14:7103–7114
    [Google Scholar]
  5. Brooks L., Yao Q. Y., Rickinson A. B., Young L. S. 1992; Epstein–Barr virus latent gene transcription in nasopharyngeal carcinoma cells: coexpression of EBNA1, LMP1, and LMP2 transcripts. J Virol 66:2689–2697
    [Google Scholar]
  6. Busson P., McCoy R., Sadler R., Gilligan K., Tursz T., Raab-Traub N. 1992; Consistent transcription of the Epstein–Barr virus LMP2 gene in nasopharyngeal carcinoma. J Virol 66:3257–3262
    [Google Scholar]
  7. Chen C. L., Sadler R. H., Walling D. M., Su A. I. J., Hsieh H. C., Raab-Traub N. 1993; Epstein–Barr virus (EBV) gene expression in EBV-positive peripheral T-cell lymphoma. J Virol 67:6303–6308
    [Google Scholar]
  8. Chen F., Zou J. Z., di Renzo L., Winberg G., Hu L. F., Klein E., Klein G., Ernberg I. 1995; A subpopulation of normal B cells latently infected with Epstein–Barr virus resembles Burkitt lymphoma cells in expressing EBNA-1 but not EBNA-2 or LMP1. J Virol 69:3752–3758
    [Google Scholar]
  9. Chen H., Lee J. M., Wang Y., Huang D. P., Ambinder R. F., Hayward S. D. 1999; The Epstein–Barr virus latency Bam HI-Q promoter is positively regulated by STATs and Zta interference with JAK/STAT activation leads to loss of Bam HI-Q promoter activity. Proc Natl Acad Sci U S A 96:9339–9344
    [Google Scholar]
  10. Chiang A. K., Tao Q., Ho F. C. 1996; Nasal NK- and T-cell lymphomas share the same type of Epstein–Barr virus latency as nasopharyngeal carcinoma and Hodgkin's disease. Int J Cancer 68:285–290
    [Google Scholar]
  11. Deacon E. M., Pallesen G., Niedobitek G., Crocker J., Brooks L., Rickinson A. B., Young L. S. 1993; Epstein–Barr virus and Hodgkin's disease: transcriptional analysis of virus latency in the malignant cells. J Exp Med 177:339–349
    [Google Scholar]
  12. Evans T. J., Farrell P. J., Swaminathan S. 1996; Molecular genetic analysis of Epstein–Barr virus Cp promoter function. J Virol 70:1695–1705
    [Google Scholar]
  13. Falk K. I., Szekely L., Aleman A., Ernberg I. 1998; Specific methylation patterns in two control regions of Epstein–Barr virus latency: the LMP-1-coding upstream regulatory region and an origin of DNA replication (oriP). J Virol 72:2969–2974
    [Google Scholar]
  14. Frommer M., Mcdonald L. E., Millar D. S., Collis C. M., Watt F., Grigg G. W., Molloy P. L., Paul C. L. 1992; A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci U S A 89:1827–1831
    [Google Scholar]
  15. Griffin B. E. 2000; Epstein–Barr virus (EBV) and human disease: facts, opinions and problems. Mutat Res 462:395–405
    [Google Scholar]
  16. Herman J. G., Graff J. R., Myohanen S., Nelkin B. D., Baylin S. B. 1996; Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A 93:9821–9826
    [Google Scholar]
  17. Imai S., Sugiura M., Oikawa O. 9 other authors 1996; Epstein–Barr virus (EBV)-carrying and -expressing T-cell lines established from severe chronic active EBV infection. Blood 87:1446–1457
    [Google Scholar]
  18. Jones J. F., Shurin S., Abramowsky C. 7 other authors 1988; T-cell lymphomas containing Epstein–Barr viral DNA in patients with chronic Epstein–Barr virus infections. N Engl J Med 318:733–741
    [Google Scholar]
  19. Kawaguchi H., Miyashita T., Herbst H. 8 other authors 1993; Epstein-Barr virus-infected T lymphocytes in Epstein–Barr virus-associated hemophagocytic syndrome. J Clin Investig 92:1444–1450
    [Google Scholar]
  20. Kieff E. 1996; Epstein–Barr virus and its replication. In Fields Virology , 3rd edn. pp  2343–2396 Edited by Fields B. N., Knipe D. M., Howley P. M. Philadelphia: Lippincott–Raven;
    [Google Scholar]
  21. Kikuta H., Taguchi Y., Tomizawa K. 12 other authors 1988; Epstein–Barr virus genome-positive T lymphocytes in a boy with chronic active EBV infection associated with Kawasaki-like disease. Nature 333:455–457
    [Google Scholar]
  22. Kikuta H., Nakanishi M., Sakiyama Y., Matsumoto S. 1989; Chronic active Epstein–Barr virus (EBV) infection is associated with clonotypic intracellular terminal regions of the EBV. J Infect Dis 160:546–547
    [Google Scholar]
  23. Kirby H., Rickinson A., Bell A. 2000; The activity of the Epstein–Barr virus Bam HI W promoter in B cells is dependent on the binding of CREB/ATF factors. J Gen Virol 81:1057–1066
    [Google Scholar]
  24. Kubota T., Das S., Christian S. L., Baylin S. B., Herman J. G., Ledbetter D. H. 1997; Methylation-specific PCR simplifies imprinting analysis. Nat Genet 16:16–17
    [Google Scholar]
  25. Laytragoon-Lewin N., Chen F., Avila-Carino J., Klein G., Mellstedt H. 1997; Epstein–Barr virus (EBV) gene expression in lymphoid B cells during acute infectious mononucleosis (IM) and clonality of the directly growing cell lines. Int J Cancer 71:345–349
    [Google Scholar]
  26. Niedobitek G., Agathanggekou A., Herbst H., Whitehead L., Wright D. H., Young L. S. 1997; Epstein–Barr virus (EBV) infection in infectious mononucleosis: virus latency, replication and phenotype of EBV-infected cells. J Pathology 182:151–159
    [Google Scholar]
  27. Nilsson T., Zetterberg H., Wang Y. C., Rymo L. 2001; Promoter-proximal regulatory elements involved in oriP -EBNA1-independent and -dependent activation of the Epstein–Barr virus C promoter in B-lymphoid cell lines. J Virol 75:5796–5811
    [Google Scholar]
  28. Ohga S., Kimura N., Takada H. 7 other authors 1999; Restricted diversification of T-cells in chronic active Epstein–Barr virus infection: potential inclination to T-lymphoproliferative disease. Am J Hemat 61:26–33
    [Google Scholar]
  29. Pallesen G., Hamilton-Dutoit S. J., Zhou X. 1993; The association of Epstein–Barr virus (EBV) with T cell lymphoproliferations and Hodgkin's disease: two new developments in the EBV field. Cancer Res 62:179–239
    [Google Scholar]
  30. Paulson E. J., Speck S. H. 1999; Differential methylation of Epstein–Barr virus latency promoters facilitates viral persistence in healthy seropositive individuals. J Virol 73:9959–9968
    [Google Scholar]
  31. Puglielli M. T., Woisetschlaeger M., Speck S. H. 1996; oriP is essential for EBNA gene promoter activity in Epstein–Barr virus-immortalized lymphoblastoid cell lines. J Virol 70:5758–5768
    [Google Scholar]
  32. Qu L., Rowe D. T. 1992; Epstein–Barr virus latent gene expression in uncultured peripheral blood lymphocytes. J Virol 66:3715–3724
    [Google Scholar]
  33. Qu L., Rowe D. T. 1995; Epstein–Barr virus latent messages with shuffled leader exons: remnants of circumgenomic transcription?. J Virol 69:1050–1058
    [Google Scholar]
  34. Rickinson A. B. 1986; Chronic, symptomatic Epstein–Barr virus infections. Immunol Today 7:13–14
    [Google Scholar]
  35. Robertson K. D., Ambinder R. F. 1997a; Mapping promoter regions that are hypersensitive to methylation-mediated inhibition of transcription: application of the methylation cassette assay to the Epstein–Barr virus major latency promoter. J Virol 71:6445–6454
    [Google Scholar]
  36. Robertson K. D., Ambinder R. F. 1997b; Methylation of the Epstein–Barr virus genome in normal lymphocytes. Blood 90:4480–4484
    [Google Scholar]
  37. Robertson K. D., Hayward S. D., Ling P. D., Samid D., Ambinder R. F. 1995; Transcriptional activation of the Epstein–Barr virus latency C promoter after 5-azacytidine treatment: evidence that demethylation at a single CpG site is crucial. Mol Cell Biol 15:6150–6159
    [Google Scholar]
  38. Robertson K. D., Manns A., Swinnen L. J., Zong J. C., Gulley M. L., Ambinder R. F. 1996; CpG methylation of the major Epstein-Barr virus latency promoter in Burkitt's lymphoma and Hodgkin's lymphoma. Blood 88:3129–3136
    [Google Scholar]
  39. Salamon D., Takacs M., Ujvari D., Uhlig J., Wolf H., Minarovits J., Niller H. 2001; Protein–DNA binding and CpG methylation at nucleotide resolution of latency-associated promoter Qp, Cp, and LMP1p of Epstein–Barr virus. J Virol 75:2584–2596
    [Google Scholar]
  40. Schaefer B. C., Strominger J. L., Speck S. H. 1995; Redefining the Epstein–Barr virus-encoded nuclear antigen EBNA-1 gene promoter and transcription site in group I Burkitt lymphoma cell lines. Proc Natl Acad Sci U S A 92:10565–10569
    [Google Scholar]
  41. Schaefer B. C., Paulson E., Strominger J. L., Speck S. H. 1997; Constitutive activation of Epstein–Barr virus (EBV) nuclear antigen 1 gene transcription by IRF1 and IRF2 during restricted EBV latency. Mol Cell Biol 17:873–886
    [Google Scholar]
  42. Schooley R. T., Carey R. W., Miller G., Henle W., Eastman R., Mark E. J., Kenyon K., Wheeler E. O., Rubin R. H. 1986; Chronic Epstein–Barr virus infection associated with fever and interstitial pneumonitis: clinical and serologic features and response to antiviral chemotherapy. Ann Intern Med 104:636–643
    [Google Scholar]
  43. Singal R., Ginder G. D. 1999; DNA methylation. Blood 93:4059–4070
    [Google Scholar]
  44. Su I. J., Chen R. L., Lin D. T., Lin K. S., Chen C. C. 1994; Epstein–Barr virus (EBV) infects T lymphocytes in childhood EBV-associated hemophagocytic syndrome in Taiwan. Am J Pathol 144:1219–1225
    [Google Scholar]
  45. Sung N. S., Wilson J., Davenport M., Sista N. D., Pagano J. S. 1994; Reciprocal regulation of the Epstein–Barr virus Bam HI-F promoter by EBNA-1 and E2F transcription factor. Mol Cell Biol 14:7144–7152
    [Google Scholar]
  46. Tao Q., Robertson K. D., Manns A., Hildesheim A., Ambinder R. F. 1998; The Epstein–Barr virus major latent promoter Qp is constitutively active, hypomethylated, and methylation sensitive. J Virol 72:7075–7083
    [Google Scholar]
  47. Tierney R. J., Steven N., Young L. S., Rickinson A. B. 1994; Epstein–Barr virus latency in blood mononuclear cells: analysis of viral gene transcription during primary infection and in the carrier state. J Virol 68:7374–7385
    [Google Scholar]
  48. Tierney R. J., Kirby H. E., Nagra J. K., Desnond J., Bell A. I., Rickinson A. B. 2000a; Methylation of transcription factor binding sites in the Epstein–Barr virus latent cycle promoter Wp coincides with promoter down-regulation during virus-induced B-cell transformation. J Virol 74:10468–10479
    [Google Scholar]
  49. Tierney R. J., Kirby H. E., Nagra J. K., Rickinson A. B., Bell A. 2000b; The Epstein–Barr virus promoter initiating B-cell transformation is activated by RFX proteins and the B-cell-specific activator protein BSAP/Pax5. J Virol 74:10458–10467
    [Google Scholar]
  50. Yoshioka M., Ishiguro M., Ishiko H., Ma X., Kikuta H., Kobayashi K. 2001; Heterogeneous, restricted patterns of Epstein–Barr virus (EBV) latent gene expression in patients with chronic active EBV infection. J Gen Virol 82:2385–2392
    [Google Scholar]
  51. Zetterberg H., Stenglein M., Jansson A., Ricksten A., Rymo L. 1999; Relative levels of EBNA1 gene transcripts from the C/W, F and Q promoters in Epstein–Barr virus-transformed lymphoid cells in latent and lytic stages of infection. J Gen Virol 80:457–465
    [Google Scholar]
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