Chronic active Epstein–Barr virus (CAEBV) infection is a systemic Epstein–Barr virus (EBV)-positive lymphoproliferative disorder characterized by persistent or recurrent infectious mononucleosis-like symptoms in patients with no known immunodeficiency. The detailed pathogenesis of the disease is unknown and no standard treatment regimen has been developed. EBV gene expression was analysed in peripheral blood samples collected from 24 patients with CAEBV infection. The expression levels of six latent and two lytic EBV genes were quantified by real-time RT-PCR. EBV-encoded small RNA 1 and HI-A rightward transcripts were abundantly detected in all patients, and latent membrane protein (LMP) 2 was observed in most patients. EBV nuclear antigen (EBNA) 1 and LMP1 were detected less frequently and were expressed at lower levels. EBNA2 and the two lytic genes were not detected in any of the patients. The pattern of latent gene expression was determined to be latency type II. EBNA1 was detected more frequently and at higher levels in the clinically active patients. Quantifying EBV gene expression is useful in clarifying the pathogenesis of CAEBV infection and may provide information regarding a patient's disease prognosis, as well as possible therapeutic interventions.


Article metrics loading...

Loading full text...

Full text loading...



  1. Arrand, J. R. & Rymo, L.(1982). Characterization of the major Epstein–Barr virus-specific RNA in Burkitt lymphoma-derived cells. J Virol 41, 376–389. [Google Scholar]
  2. Bell, A. I., Groves, K., Kelly, G. L., Croom-Carter, D., Hui, E., Chan, A. T. & Rickinson, A. B.(2006). Analysis of Epstein–Barr virus latent gene expression in endemic Burkitt's lymphoma and nasopharyngeal carcinoma tumour cells by using quantitative real-time PCR assays. J Gen Virol 87, 2885–2890.[CrossRef] [Google Scholar]
  3. Bollard, C. M., Aguilar, L., Straathof, K. C., Gahn, B., Huls, M. H., Rousseau, A., Sixbey, J., Gresik, M. V., Carrum, G. & other authors(2004). Cytotoxic T lymphocyte therapy for Epstein–Barr virus+ Hodgkin's disease. J Exp Med 200, 1623–1633.[CrossRef] [Google Scholar]
  4. Bollard, C. M., Gottschalk, S., Leen, A. M., Weiss, H., Straathof, K. C., Carrum, G., Khalil, M., Wu, M. F., Huls, M. H. & other authors(2007). Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer. Blood 110, 2838–2845.[CrossRef] [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. Cohen, J. I.(2000). Epstein–Barr virus infection. N Engl J Med 343, 481–492.[CrossRef] [Google Scholar]
  7. 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.[CrossRef] [Google Scholar]
  8. Fujii, N., Takenaka, K., Hiraki, A., Maeda, Y., Ikeda, K., Shinagawa, K., Ashiba, A., Munemasa, M., Sunami, K. & other authors(2000). Allogeneic peripheral blood stem cell transplantation for the treatment of chronic active Epstein-Barr virus infection. Bone Marrow Transplant 26, 805–808.[CrossRef] [Google Scholar]
  9. Gotoh, K., Ito, Y., Shibata-Watanabe, Y., Kawada, J., Takahashi, Y., Yagasaki, H., Kojima, S., Nishiyama, Y. & Kimura, H.(2008). Clinical and virological characteristics of 15 patients with chronic active Epstein–Barr virus infection treated with hematopoietic stem cell transplantation. Clin Infect Dis 46, 1525–1534.[CrossRef] [Google Scholar]
  10. Hagihara, M., Tsuchiya, T., Hyodo, O., Ueda, Y., Tazume, K., Masui, A., Kanemura, A., Yoshiba, F., Takashimizu, S. & other authors(2003). Clinical effects of infusing anti-Epstein–Barr virus (EBV)-specific cytotoxic T-lymphocytes into patients with severe chronic active EBV infection. Int J Hematol 78, 62–68.[CrossRef] [Google Scholar]
  11. Heslop, H. E., Ng, C. Y., Li, C., Smith, C. A., Loftin, S. K., Krance, R. A., Brenner, M. K. & Rooney, C. M.(1996). Long-term restoration of immunity against Epstein–Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nat Med 2, 551–555.[CrossRef] [Google Scholar]
  12. Hislop, A. D., Taylor, G. S., Sauce, D. & Rickinson, A. B.(2007). Cellular responses to viral infection in humans: lessons from Epstein–Barr virus. Annu Rev Immunol 25, 587–617.[CrossRef] [Google Scholar]
  13. Kanegane, H., Nomura, K., Miyawaki, T. & Tosato, G.(2002). Biological aspects of Epstein–Barr virus (EBV)-infected lymphocytes in chronic active EBV infection and associated malignancies. Crit Rev Oncol Hematol 44, 239–249.[CrossRef] [Google Scholar]
  14. Kieff, E. D. & Rickinson, A. V.(2007). Epstein–Barr virus and its replication. In Fields Virology, pp. 2603–2654. Edited by D. M. Knipe & P. M. Howley. Philadelphia: Lippincott Williams & Wilkins.
  15. Kimura, H.(2006). Pathogenesis of chronic active Epstein–Barr virus infection: is this an infectious disease, lymphoproliferative disorder, or immunodeficiency? Rev Med Virol 16, 251–261.[CrossRef] [Google Scholar]
  16. Kimura, H., Morita, M., Yabuta, Y., Kuzushima, K., Kato, K., Kojima, S., Matsuyama, T. & Morishima, T.(1999). Quantitative analysis of Epstein–Barr virus load by using a real-time PCR assay. J Clin Microbiol 37, 132–136. [Google Scholar]
  17. Kimura, H., Hoshino, Y., Kanegane, H., Tsuge, I., Okamura, T., Kawa, K. & Morishima, T.(2001). Clinical and virologic characteristics of chronic active Epstein-Barr virus infection. Blood 98, 280–286.[CrossRef] [Google Scholar]
  18. Kimura, H., Morishima, T., Kanegane, H., Ohga, S., Hoshino, Y., Maeda, A., Imai, S., Okano, M., Morio, T. & other authors(2003). Prognostic factors for chronic active Epstein–Barr virus infection. J Infect Dis 187, 527–533.[CrossRef] [Google Scholar]
  19. Kimura, H., Hoshino, Y., Hara, S., Sugaya, N., Kawada, J., Shibata, Y., Kojima, S., Nagasaka, T., Kuzushima, K. & Morishima, T.(2005). Differences between T cell-type and natural killer cell-type chronic active Epstein–Barr virus infection. J Infect Dis 191, 531–539.[CrossRef] [Google Scholar]
  20. Kubota, N., Wada, K., Ito, Y., Shimoyama, Y., Nakamura, S., Nishiyama, Y. & Kimura, H.(2008). One-step multiplex real-time PCR assay to analyse the latency patterns of Epstein–Barr virus infection. J Virol Methods 147, 26–36.[CrossRef] [Google Scholar]
  21. Kuzushima, K., Yamamoto, M., Kimura, H., Ando, Y., Kudo, T., Tsuge, I. & Morishima, T.(1996). Establishment of anti-Epstein–Barr virus (EBV) cellular immunity by adoptive transfer of virus-specific cytotoxic T lymphocytes from an HLA-matched sibling to a patient with severe chronic active EBV infection. Clin Exp Immunol 103, 192–198.[CrossRef] [Google Scholar]
  22. Kwon, J. M., Park, Y. H., Kang, J. H., Kim, K., Ko, Y. H., Ryoo, B. Y., Lee, S. S., Lee, S. I., Koo, H. H. & Kim, W. S.(2006). The effect of Epstein–Barr virus status on clinical outcome in Hodgkin's lymphoma. Ann Hematol 85, 463–468.[CrossRef] [Google Scholar]
  23. Leenman, E. E., Panzer-Grumayer, R. E., Fischer, S., Leitch, H. A., Horsman, D. E., Lion, T., Gadner, H., Ambros, P. F. & Lestou, V. S.(2004). Rapid determination of Epstein–Barr virus latent or lytic infection in single human cells using in situ hybridization. Mod Pathol 17, 1564–1572.[CrossRef] [Google Scholar]
  24. Okamura, T., Hatsukawa, Y., Arai, H., Inoue, M. & Kawa, K.(2000). Blood stem-cell transplantation for chronic active Epstein–Barr virus with lymphoproliferation. Lancet 356, 223–224.[CrossRef] [Google Scholar]
  25. Okano, M., Kawa, K., Kimura, H., Yachie, A., Wakiguchi, H., Maeda, A., Imai, S., Ohga, S., Kanegane, H. & other authors(2005). Proposed guidelines for diagnosing chronic active Epstein–Barr virus infection. Am J Hematol 80, 64–69.[CrossRef] [Google Scholar]
  26. Patel, K., Whelan, P. J., Prescott, S., Brownhill, S. C., Johnston, C. F., Selby, P. J. & Burchill, S. A.(2004). The use of real-time reverse transcription-PCR for prostate-specific antigen mRNA to discriminate between blood samples from healthy volunteers and from patients with metastatic prostate cancer. Clin Cancer Res 10, 7511–7519.[CrossRef] [Google Scholar]
  27. Quintanilla-Martinez, L., Kumar, S., Fend, F., Reyes, E., Teruya-Feldstein, J., Kingma, D. W., Sorbara, L., Raffeld, M., Straus, S. E. & Jaffe, E. S.(2000). Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome. Blood 96, 443–451. [Google Scholar]
  28. Rickinson, A. B. & Kieff, E.(2007). Epstein–Barr virus. In Fields Virology, pp. 2655–2700. Edited by D. M. Knipe & P. M. Howley. Philadelphia: Lippincott Williams & Wilkins.
  29. Rooney, C. M., Smith, C. A., Ng, C. Y., Loftin, S. K., Sixbey, J. W., Gan, Y., Srivastava, D. K., Bowman, L. C., Krance, R. A. & other authors(1998). Infusion of cytotoxic T cells for the prevention and treatment of Epstein–Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 92, 1549–1555. [Google Scholar]
  30. Saridakis, V., Sheng, Y., Sarkari, F., Holowaty, M. N., Shire, K., Nguyen, T., Zhang, R. G., Liao, J., Lee, W. & other authors(2005). Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein–Barr nuclear antigen 1 implications for EBV-mediated immortalization. Mol Cell 18, 25–36.[CrossRef] [Google Scholar]
  31. Savoldo, B., Huls, M. H., Liu, Z., Okamura, T., Volk, H. D., Reinke, P., Sabat, R., Babel, N., Jones, J. F. & other authors(2002). Autologous Epstein–Barr virus (EBV)-specific cytotoxic T cells for the treatment of persistent active EBV infection. Blood 100, 4059–4066.[CrossRef] [Google Scholar]
  32. Straathof, K. C., Leen, A. M., Buza, E. L., Taylor, G., Huls, M. H., Heslop, H. E., Rooney, C. M. & Bollard, C. M.(2005). Characterization of latent membrane protein 2 specificity in CTL lines from patients with EBV-positive nasopharyngeal carcinoma and lymphoma. J Immunol 175, 4137–4147.[CrossRef] [Google Scholar]
  33. Straus, S. E.(1988). The chronic mononucleosis syndrome. J Infect Dis 157, 405–412.[CrossRef] [Google Scholar]
  34. Sugaya, N., Kimura, H., Hara, S., Hoshino, Y., Kojima, S., Morishima, T., Tsurumi, T. & Kuzushima, K.(2004). Quantitative analysis of Epstein–Barr virus (EBV)-specific CD8+ T cells in patients with chronic active EBV infection. J Infect Dis 190, 985–988.[CrossRef] [Google Scholar]
  35. Taketani, T., Kikuchi, A., Inatomi, J., Hanada, R., Kawaguchi, H., Ida, K., Oh-Ishi, T., Arai, T., Kishimoto, H. & Yamamoto, K.(2002). Chronic active Epstein–Barr virus infection (CAEBV) successfully treated with allogeneic peripheral blood stem cell transplantation. Bone Marrow Transplant 29, 531–533.[CrossRef] [Google Scholar]
  36. Tao, Q., Robertson, K. D., Manns, A., Hildesheim, A. & Ambinder, R. F.(1998). Epstein–Barr virus (EBV) in endemic Burkitt's lymphoma: molecular analysis of primary tumor tissue. Blood 91, 1373–1381. [Google Scholar]
  37. Thorley-Lawson, D. A. & Gross, A.(2004). Persistence of the Epstein–Barr virus and the origins of associated lymphomas. N Engl J Med 350, 1328–1337.[CrossRef] [Google Scholar]
  38. Tosato, G., Straus, S., Henle, W., Pike, S. E. & Blaese, R. M.(1985). Characteristic T cell dysfunction in patients with chronic active Epstein–Barr virus infection (chronic infectious mononucleosis). J Immunol 134, 3082–3088. [Google Scholar]
  39. Tsang, N. M., Chuang, C. C., Tseng, C. K., Hao, S. P., Kuo, T. T., Lin, C. Y. & Pai, P. C.(2003). Presence of the latent membrane protein 1 gene in nasopharyngeal swabs from patients with mucosal recurrent nasopharyngeal carcinoma. Cancer 98, 2385–2392.[CrossRef] [Google Scholar]
  40. Tsuge, I., Morishima, T., Morita, M., Kimura, H., Kuzushima, K. & Matsuoka, H.(1999). Characterization of Epstein–Barr virus (EBV)-infected natural killer (NK) cell proliferation in patients with severe mosquito allergy; establishment of an IL-2-dependent NK-like cell line. Clin Exp Immunol 115, 385–392.[CrossRef] [Google Scholar]
  41. Weinberger, B., Plentz, A., Weinberger, K. M., Hahn, J., Holler, E. & Jilg, W.(2004). Quantitation of Epstein–Barr virus mRNA using reverse transcription and real-time PCR. J Med Virol 74, 612–618.[CrossRef] [Google Scholar]
  42. Williams, H. & Crawford, D. H.(2006). Epstein–Barr virus: the impact of scientific advances on clinical practice. Blood 107, 862–869. [Google Scholar]
  43. Young, L., Alfieri, C., Hennessy, K., Evans, H., O'Hara, C., Anderson, K. C., Ritz, J., Shapiro, R. S., Rickinson, A. & other authors(1989). Expression of Epstein–Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease. N Engl J Med 321, 1080–1085.[CrossRef] [Google Scholar]
  44. Zhang, Y., Nagata, H., Ikeuchi, T., Mukai, H., Oyoshi, M. K., Demachi, A., Morio, T., Wakiguchi, H., Kimura, N. & other authors(2003). Common cytological and cytogenetic features of Epstein–Barr virus (EBV)-positive natural killer (NK) cells and cell lines derived from patients with nasal T/NK-cell lymphomas, chronic active EBV infection and hydroa vacciniforme-like eruptions. Br J Haematol 121, 805–814.[CrossRef] [Google Scholar]

Data & Media loading...

Most cited this month Most Cited RSS feed

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