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Epstein–Barr virus: more than 50 years old and still providing surprises

Abstract

It is more than 50 years since the Epstein–Barr virus (EBV), the first human tumour virus, was discovered. EBV has subsequently been found to be associated with a diverse range of tumours of both lymphoid and epithelial origin. Progress in the molecular analysis of EBV has revealed fundamental mechanisms of more general relevance to the oncogenic process. This Timeline article highlights key milestones in the 50-year history of EBV and discusses how this virus provides a paradigm for exploiting insights at the molecular level in the diagnosis, treatment and prevention of cancer.

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Figure 1: Timeline showing the major milestones in EBV research.
Figure 2: EBV and its latent genes in 2016.
Figure 3: Virus persistence in the B cells of the human host and the origin of EBV-associated B cell lymphomas.
Figure 4: Schematic representation of the pathogenesis of NPC.

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References

  1. De Martel, C. et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol. 13, 607–615 (2012).

    PubMed  Google Scholar 

  2. Khan, G. & Hashim, M. J. Global burden of deaths from Epstein–Barr virus: attributable malignancies 1990–2010. Infect. Agent. Cancer 9, 38 (2014).

    PubMed Central  PubMed  Google Scholar 

  3. Crawford, D. H., Rickinson, A. B. & Johannessen, I. in Cancer Virus: The Story of Epstein–Barr Virus (Oxford Univ. Press, 2014).

    Google Scholar 

  4. Tsao, S. W., Tsang, C. M., To, K. F. & Lo, K. W. The role of Epstein–Barr virus in epithelial malignancies. J. Pathol. 235, 323–333 (2015).

    CAS  PubMed  Google Scholar 

  5. Pasteur, L. Inaugural address as newly appointed Professor and Dean at the opening of the new Faculte des Sciences, Univ. Lille (7 Dec 1854).

  6. Epstein, M. A. On the discovery of Epstein–Barr virus: a memoir. Epstein–Barr Virus Rep. 6, 58–63 (1999).

    Google Scholar 

  7. Epstein, M. A., Achong, B. G. & Barr, Y. M. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet 1, 702–703 (1964).

    CAS  PubMed  Google Scholar 

  8. Epstein, M. A. Citation classic – Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Curr. Contents Life Sci. 14, 156 (1979).

    Google Scholar 

  9. Pope, J. H., Achong, B. G., Epstein, M. A. & Biddulph, J. Burkitt lymphoma in New Guinea: establishment of a line of lymphoblasts in vitro and description of their fine structure. J. Natl Cancer Inst. 39, 933–945 (1967).

    CAS  PubMed  Google Scholar 

  10. Henle, W., Diehl, V., Kohn, G., Zur Hausen, H. & Henle, G. Herpes-type virus and chromosome marker in normal leukocytes after growth with irradiated Burkitt cells. Science 157, 1064–1065 (1967).

    CAS  PubMed  Google Scholar 

  11. Pope, J. H. Establishment of cell lines from peripheral leucocytes in infectious mononucleosis. Nature 216, 810–811 (1967).

    CAS  PubMed  Google Scholar 

  12. Pope, J. H., Horne, M. K. & Scott, W. Transformation of foetal human keukocytes in vitro by filtrates of a human leukaemic cell line containing herpes-like virus. Int. J. Cancer 3, 857–866 (1968).

    CAS  PubMed  Google Scholar 

  13. Henderson, E., Miller, G., Robinson, J. & Heston, L. Efficiency of transformation of lymphocytes by Epstein–Barr virus. Virology 76, 152–163 (1977).

    CAS  PubMed  Google Scholar 

  14. Sugden, B. & Mark, W. Clonal transformation of adult human leukocytes by Epstein–Barr virus. J. Virol. 23, 503–508 (1977).

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Thorley-Lawson, D. A. & Allday, M. J. The curious case of the tumour virus: 50 years of Burkitt's lymphoma. Nat. Rev. Microbiol. 6, 913–924 (2008).

    CAS  PubMed  Google Scholar 

  16. Baer, R. et al. DNA sequence and expression of the B95-8 Epstein–Barr virus genome. Nature 310, 207–211 (1984).

    CAS  PubMed  Google Scholar 

  17. Dambaugh, T., Hennessy, K., Chamnankit, L. & Kieff, E. U2 region of Epstein–Barr virus DNA may encode Epstein–Barr nuclear antigen 2. Proc. Natl Acad. Sci. USA 81, 7632–7636 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Sample, J. et al. Epstein–Barr virus types 1 and 2 differ in their EBNA-3A, EBNA-3B, and EBNA-3C genes. J. Virol. 64, 4084–4092 (1990).

    CAS  PubMed Central  PubMed  Google Scholar 

  19. de Jesus, O. et al. Updated Epstein–Barr virus (EBV) DNA sequence and analysis of a promoter for the BART (CST, BARF0) RNAs of EBV. J. Gen. Virol. 84, 1443–1450 (2003).

    CAS  PubMed  Google Scholar 

  20. Zeng, M. S. et al. Genomic sequence analysis of Epstein–Barr virus strain GD1 from a nasopharyngeal carcinoma patient. J. Virol. 79, 15323–15330 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Dolan, A., Addison, C., Gatherer, D., Davison, A. J. & McGeoch, D. J. The genome of Epstein–Barr virus type 2 strain AG876. Virology 350, 164–170 (2006).

    CAS  PubMed  Google Scholar 

  22. Liu, P. et al. Direct sequencing and characterization of a clinical isolate of Epstein–Barr virus from nasopharyngeal carcinoma tissue by using next-generation sequencing technology. J. Virol. 85, 11291–11299 (2011).

    PubMed Central  PubMed  Google Scholar 

  23. Kwok, H. et al. Genomic sequencing and comparative analysis of Epstein–Barr virus genome isolated from primary nasopharyngeal carcinoma biopsy. PLoS ONE 7, e36939 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Lin, Z. et al. Whole-genome sequencing of the Akata and Mutu Epstein–Barr virus strains. J. Virol. 87, 1172–1182 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Tsai, M. H. et al. Spontaneous lytic replication and epitheliotropism define an Epstein–Barr virus strain found in carcinomas. Cell Rep. 5, 458–470 (2013).

    CAS  PubMed  Google Scholar 

  26. Lei, H. et al. Identification and characterization of EBV genomes in spontaneously immortalized human peripheral blood B lymphocytes by NGS technology. BMC Genomics 14, 804 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Kwok, H. et al. Genomic diversity of Epstein–Barr virus genomes isolated from primary nasopharyngeal carcinoma biopsy samples. J. Virol. 88, 10662–10672 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Santpere, G. et al. Genome-wide analysis of wild-type Epstein–Barr virus genomes derived from healthy individuals of the 1,000 Genomes project. Genome Biol. Evol. 6, 846–860 (2014).

    PubMed Central  PubMed  Google Scholar 

  29. Palser, A. L. et al. Genome diversity of Epstein–Barr virus from multiple tumor types and normal infection. J. Virol. 89, 5222–5237 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Rowe, M. et al. Differences in B cell growth phenotype reflect novel patterns of Epstein–Barr virus latent gene expression in Burkitt's lymphoma cells. EMBO J. 6, 2743–2751 (1987).

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Rowe, M., Lear, A. L., Croom-Carter, D., Davies, A. H. & Rickinson, A. B. Three pathways of Epstein–Barr virus gene activation from EBNA1-positive latency in B lymphocytes. J. Virol. 66, 122–131 (1992).

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Young, L. S. et al. Epstein–Barr virus gene expression in nasopharyngeal carcinoma. J. Gen. Virol. 69, 1051–1065 (1988).

    CAS  PubMed  Google Scholar 

  33. Imai, S. et al. Gastric carcinoma: monoclonal epithelial malignant cells expressing Epstein–Barr virus latent infection protein. Proc. Natl Acad. Sci. USA 91, 9131–9135 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. zur Hausen, H., O'Neill, F. J., Freese, U. K. & Hecker, E. Persisting oncogenic herpesvirus induced by the tumour promoter TPA. Nature 272, 373–375 (1978).

    CAS  PubMed  Google Scholar 

  35. Kallin, B., Luka, J. & Klein, G. Immunochemical characterization of Epstein–Barr virus-associated early and late antigens in n-butyrate-treated P3HR-1 cells. J. Virol. 32, 710–716 (1979).

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Countryman, J. & Miller, G. Activation of expression of latent Epstein–Barr herpesvirus after gene transfer with a small cloned subfragment of heterogeneous viral DNA. Proc. Natl Acad. Sci. USA 82, 4085–4089 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Bhende, P. M., Dickerson, S. J., Sun, X., Feng, W. H. & Kenney, S. C. X-Box-binding protein 1 activates lytic Epstein–Barr virus gene expression in combination with protein kinase D. J. Virol. 81, 7363–7370 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Sun, C. C. & Thorley-Lawson, D. A. Plasma cell-specific transcription factor XBP-1s binds to and transactivates the Epstein–Barr virus BZLF1 promoter. J. Virol. 81, 13566–13577 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Temple, R. M. et al. Efficient replication of Epstein–Barr virus in stratified epithelium in vitro. Proc. Natl Acad. Sci. USA 111, 16544–16549 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Old, L. J. et al. Precipitating antibody in human serum to an antigen present in cultured Burkitt's lymphoma cells. Proc. Natl Acad. Sci. USA 56, 1699–1704 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Levy, J. A. & Henle, G. Indirect immunofluorescence tests with sera from African children and cultured Burkitt lymphoma cells. J. Bacteriol. 92, 275–276 (1966).

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Henle, G. & Henle, W. Immunofluorescence in cells derived from Burkitt's lymphoma. J. Bacteriol. 91, 1248–1256 (1966).

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Henle, G. et al. Antibodies to Epstein–Barr virus in Burkitt's lymphoma and control groups. J. Natl Cancer Inst. 43, 1147–1157 (1969).

    CAS  PubMed  Google Scholar 

  44. de-The, G. et al. Epidemiological evidence for causal relationship between Epstein–Barr virus and Burkitt's lymphoma from Ugandan prospective study. Nature 274, 756–761 (1978).

    CAS  PubMed  Google Scholar 

  45. Whittle, H. C. et al. T-cell control of Epstein–Barr virus-infected B cells is lost during P. falciparum malaria. Nature 312, 449–450 (1984).

    CAS  PubMed  Google Scholar 

  46. Moormann, A. M. et al. Exposure to holoendemic malaria results in suppression of Epstein–Barr virus-specific T cell immunosurveillance in Kenyan children. J. Infect. Dis. 195, 799–808 (2007).

    CAS  PubMed  Google Scholar 

  47. Moormann, A. M., Snider, C. J. & Chelimo, K. The company malaria keeps: how co-infection with Epstein–Barr virus leads to endemic Burkitt lymphoma. Curr. Opin. Infect. Dis. 24, 435–441 (2011).

    PubMed Central  PubMed  Google Scholar 

  48. Horne-Debets, J. M. et al. PD-1 dependent exhaustion of CD8+ T cells drives chronic malaria. Cell Rep. 5, 1204–1213 (2013).

    CAS  PubMed  Google Scholar 

  49. Moss, D. J. et al. A comparison of Epstein–Barr virus-specific T-cell immunity in malaria-endemic and -nonendemic regions of Papua New Guinea. Int. J. Cancer 31, 727–732 (1983).

    CAS  PubMed  Google Scholar 

  50. Njie, R. et al. The effects of acute malaria on Epstein–Barr virus (EBV) load and EBV-specific T cell immunity in Gambian children. J. Infect. Dis. 199, 31–38 (2009).

    PubMed  Google Scholar 

  51. Torgbor, C. et al. A multifactorial role for P. falciparum malaria in endemic Burkitt's lymphoma pathogenesis. PLoS Pathog. 10, e1004170 (2014).

    PubMed Central  PubMed  Google Scholar 

  52. Wilmore, J. R. et al. AID expression in peripheral blood of children living in a malaria holoendemic region is associated with changes in B cell subsets and Epstein–Barr virus. Int. J. Cancer 136, 1371–1380 (2015).

    CAS  PubMed  Google Scholar 

  53. MacNeil, A., Sumba, O. P., Lutzke, M. L., Moormann, A. & Rochford, R. Activation of the Epstein–Barr virus lytic cycle by the latex of the plant Euphorbia tirucalli. Br. J. Cancer 88, 1566–1569 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Mannucci, S. et al. EBV reactivation and chromosomal polysomies: Euphorbia tirucalli as a possible cofactor in endemic Burkitt lymphoma. Adv. Hematol. 2012, 149780 (2012).

    PubMed Central  PubMed  Google Scholar 

  55. zur Hausen, H. et al. EBV DNA in biopsies of Burkitt tumours and anaplastic carcinomas of the nasopharynx. Nature 228, 1056–1058 (1970).

    CAS  PubMed  Google Scholar 

  56. Reedman, B. M. et al. Epstein–Barr virus-associated complement-fixing and nuclear antigens in Burkitt lymphoma biopsies. Int. J. Cancer 13, 755–763 (1974).

    CAS  PubMed  Google Scholar 

  57. Dillner, J. et al. Antibodies against a synthetic peptide identify the Epstein–Barr virus-determined nuclear antigen. Proc. Natl Acad. Sci. USA 81, 4652–4656 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Dillner, J., Kallin, B., Ehlin-Henriksson, B., Timar, L. & Klein, G. Characterization of a second Epstein–Barr virus-determined nuclear antigen associated with the BamHI WYH region of EBV DNA. Int. J. Cancer 35, 359–366 (1985).

    CAS  PubMed  Google Scholar 

  59. Manolov, G. & Manolova, Y. Marker band in one chromosome 14 from Burkitt lymphomas. Nature 237, 33–34 (1972).

    CAS  PubMed  Google Scholar 

  60. Zech, L., Haglund, U., Nilsson, K. & Klein, G. Characteristic chromosomal abnormalities in biopsies and lymphoid-cell lines from patients with Burkitt and non-Burkitt lymphomas. Int. J. Cancer 17, 47–56 (1976).

    CAS  PubMed  Google Scholar 

  61. Bernheim, A., Berger, R. & Lenoir, G. [Translocations t(2;8) and t(8;22) in continuous cell lines of African Burkitt's lymphoma]. C. R. Seances Acad. Sci. D 291, 237–239 (1980).

    CAS  PubMed  Google Scholar 

  62. Erikson, J., ar-Rushdi, A., Drwinga, H. L., Nowell, P. C. & Croce, C. M. Transcriptional activation of the translocated c-myc oncogene in Burkitt lymphoma. Proc. Natl Acad. Sci. USA 80, 820–824 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Armelin, H. A. et al. Functional role for c-myc in mitogenic response to platelet-derived growth factor. Nature 310, 655–660 (1984).

    CAS  PubMed  Google Scholar 

  64. Einat, M., Resnitzky, D. & Kimchi, A. Close link between reduction of c-myc expression by interferon and, G0/G1 arrest. Nature 313, 597–600 (1985).

    CAS  PubMed  Google Scholar 

  65. Evan, G. I. et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell 69, 119–128 (1992).

    CAS  PubMed  Google Scholar 

  66. Milner, A. E., Grand, R. J., Waters, C. M. & Gregory, C. D. Apoptosis in Burkitt lymphoma cells is driven by c-myc. Oncogene 8, 3385–3391 (1993).

    CAS  PubMed  Google Scholar 

  67. Shimizu, N., Tanabe-Tochikura, A., Kuroiwa, Y. & Takada, K. Isolation of Epstein–Barr virus (EBV)-negative cell clones from the EBV-positive Burkitt's lymphoma (BL) line Akata: malignant phenotypes of BL cells are dependent on EBV. J. Virol. 68, 6069–6073 (1994).

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Kennedy, G., Komano, J. & Sugden, B. Epstein–Barr virus provides a survival factor to Burkitt's lymphomas. Proc. Natl Acad. Sci. USA 100, 14269–14274 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Ruf, I. K. et al. Epstein–Barr virus regulates c-MYC, apoptosis, and tumorigenicity in Burkitt lymphoma. Mol. Cell. Biol. 19, 1651–1660 (1999).

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Komano, J., Maruo, S., Kurozumi, K., Oda, T. & Takada, K. Oncogenic role of Epstein–Barr virus-encoded RNAs in Burkitt's lymphoma cell line Akata. J. Virol. 73, 9827–9831 (1999).

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Jochner, N. et al. Epstein–Barr virus nuclear antigen 2 is a transcriptional suppressor of the immunoglobulin mu gene: implications for the expression of the translocated c-myc gene in Burkitt's lymphoma cells. EMBO J. 15, 375–382 (1996).

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Pajic, A. et al. Antagonistic effects of c-myc and Epstein–Barr virus latent genes on the phenotype of human B cells. Int. J. Cancer 93, 810–816 (2001).

    CAS  PubMed  Google Scholar 

  73. Kelly, G., Bell, A. & Rickinson, A. Epstein–Barr virus-associated Burkitt lymphomagenesis selects for downregulation of the nuclear antigen EBNA2. Nat. Med. 8, 1098–1104 (2002).

    CAS  PubMed  Google Scholar 

  74. Kelly, G. L. et al. Epstein–Barr virus nuclear antigen 2 (EBNA2) gene deletion is consistently linked with EBNA3A, -3B, and -3C expression in Burkitt's lymphoma cells and with increased resistance to apoptosis. J. Virol. 79, 10709–10717 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Anderton, E. et al. Two Epstein–Barr virus (EBV) oncoproteins cooperate to repress expression of the proapoptotic tumour-suppressor Bim: clues to the pathogenesis of Burkitt's lymphoma. Oncogene 27, 421–433 (2008).

    CAS  PubMed  Google Scholar 

  76. Kelly, G. L. et al. An Epstein–Barr virus anti-apoptotic protein constitutively expressed in transformed cells and implicated in Burkitt lymphomagenesis: the Wp/BHRF1 link. PLoS Pathog. 5, e1000341 (2009).

    PubMed Central  PubMed  Google Scholar 

  77. Tierney, R. J., Shannon-Lowe, C. D., Fitzsimmons, L., Bell, A. I. & Rowe, M. Unexpected patterns of Epstein–Barr virus transcription revealed by a high throughput PCR array for absolute quantification of viral mRNA. Virology 474, 117–130 (2015).

    CAS  PubMed  Google Scholar 

  78. Henle, G., Henle, W. & Diehl, V. Relation of Burkitt's tumor-associated herpes-type virus to infectious mononucleosis. Proc. Natl Acad. Sci. USA 59, 94–101 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Niederman, J. C., Miller, G., Pearson, H. A., Pagano, J. S. & Dowaliby, J. M. Infectious mononucleosis. Epstein–Barr-virus shedding in saliva and the oropharynx. N. Engl. J. Med. 294, 1355–1359 (1976).

    CAS  PubMed  Google Scholar 

  80. Greenspan, J. S. et al. Replication of Epstein–Barr virus within the epithelial cells of oral “hairy” leukoplakia, an AIDS-associated lesion. N. Engl. J. Med. 313, 1564–1571 (1985).

    CAS  PubMed  Google Scholar 

  81. Babcock, G. J., Decker, L. L., Volk, M. & Thorley-Lawson, D. A. EBV persistence in memory B cells in vivo. Immunity 9, 395–404 (1998).

    CAS  PubMed  Google Scholar 

  82. Kurth, J. et al. EBV-infected B cells in infectious mononucleosis: viral strategies for spreading in the B cell compartment and establishing latency. Immunity 13, 485–495 (2000).

    CAS  PubMed  Google Scholar 

  83. Kurth, J., Hansmann, M. L., Rajewsky, K. & Kuppers, R. Epstein–Barr virus-infected B cells expanding in germinal centers of infectious mononucleosis patients do not participate in the germinal center reaction. Proc. Natl Acad. Sci. USA 100, 4730–4735 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Thorley-Lawson, D. A. & Gross, A. Persistence of the Epstein–Barr virus and the origins of associated lymphomas. N. Engl. J. Med. 350, 1328–1337 (2004).

    CAS  PubMed  Google Scholar 

  85. Gires, O. et al. Latent membrane protein 1 of Epstein–Barr virus mimics a constitutively active receptor molecule. EMBO J. 16, 6131–6140 (1997).

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Caldwell, R. G., Wilson, J. B., Anderson, S. J. & Longnecker, R. Epstein–Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity 9, 405–411 (1998).

    CAS  PubMed  Google Scholar 

  87. Babcock, G. J., Hochberg, D. & Thorley-Lawson, A. D. The expression pattern of Epstein–Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity 13, 497–506 (2000).

    CAS  PubMed  Google Scholar 

  88. Thorley-Lawson, D. A. Epstein–Barr virus: exploiting the immune system. Nat. Rev. Immunol. 1, 75–82 (2001).

    CAS  PubMed  Google Scholar 

  89. Panagopoulos, D., Victoratos, P., Alexiou, M., Kollias, G. & Mosialos, G. Comparative analysis of signal transduction by CD40 and the Epstein–Barr virus oncoprotein LMP1 in vivo. J. Virol. 78, 13253–13261 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Swanson-Mungerson, M. A., Caldwell, R. G., Bultema, R. & Longnecker, R. Epstein–Barr virus LMP2A alters in vivo and in vitro models of B-cell anergy, but not deletion, in response to autoantigen. J. Virol. 79, 7355–7362 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Thorley-Lawson, D. A., Duca, K. A. & Shapiro, M. Epstein–Barr virus: a paradigm for persistent infection — for real and in virtual reality. Trends Immunol. 29, 195–201 (2008).

    CAS  PubMed  Google Scholar 

  92. Roughan, J. E. & Thorley-Lawson, D. A. The intersection of Epstein–Barr virus with the germinal center. J. Virol. 83, 3968–3976 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Roughan, J. E., Torgbor, C. & Thorley-Lawson, D. A. Germinal center B cells latently infected with Epstein–Barr virus proliferate extensively but do not increase in number. J. Virol. 84, 1158–1168 (2010).

    CAS  PubMed  Google Scholar 

  94. Laichalk, L. L. & Thorley-Lawson, D. A. Terminal differentiation into plasma cells initiates the replicative cycle of Epstein–Barr virus in vivo. J. Virol. 79, 1296–1307 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Sheldon, P. J., Hemsted, E. H., Papamichail, M. & Holborow, E. J. Thymic origin of atypical lymphoid cells in infectious mononucleosis. Lancet 1, 1153–1155 (1973).

    CAS  PubMed  Google Scholar 

  96. Pattengale, P. K., Smith, R. W. & Perlin, E. Atypical lymphocytes in acute infectious mononucleosis. Identification by multiple T and B lymphocyte markers. N. Engl. J. Med. 291, 1145–1148 (1974).

    CAS  PubMed  Google Scholar 

  97. Moss, D. J., Rickinson, A. B. & Pope, J. H. Long-term T-cell-mediated immunity to Epstein–Barr virus in man. I. Complete regression of virus-induced transformation in cultures of seropositive donor leukocytes. Int. J. Cancer 22, 662–668 (1978).

    CAS  PubMed  Google Scholar 

  98. Rickinson, A. B., Moss, D. J. & Pope, J. H. Long-term C-cell-mediated immunity to Epstein–Barr virus in man. II. Components necessary for regression in virus-infected leukocyte cultures. Int. J. Cancer 23, 610–617 (1979).

    CAS  PubMed  Google Scholar 

  99. Moss, D. J. et al. Cytotoxic T-cell clones discriminate between A- and B-type Epstein–Barr virus transformants. Nature 331, 719–721 (1988).

    CAS  PubMed  Google Scholar 

  100. Burrows, S. R., Sculley, T. B., Misko, I. S., Schmidt, C. & Moss, D. J. An Epstein–Barr virus-specific cytotoxic T cell epitope in EBV nuclear antigen 3 (EBNA 3). J. Exp. Med. 171, 345–349 (1990).

    CAS  PubMed  Google Scholar 

  101. Kanekiyo, M. et al. Rational design of an Epstein–Barr virus vaccine targeting the receptor-binding site. Cell 162, 1090–1100 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Hui, E. P. et al. Phase I trial of recombinant modified vaccinia ankara encoding Epstein–Barr viral tumor antigens in nasopharyngeal carcinoma patients. Cancer Res. 73, 1676–1688 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Sokal, E. M. et al. Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein–Barr virus vaccine in healthy young adults. J. Infect. Dis. 196, 1749–1753 (2007).

    PubMed  Google Scholar 

  104. Doak, P. B., Montgomerie, J. Z., North, J. D. & Smith, F. Reticulum cell sarcoma after renal homotransplantation and azathioprine and prednisone therapy. Br. Med. J. 4, 746–748 (1968).

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Penn, I., Hammond, W., Brettschneider, L. & Starzl, T. E. Malignant lymphomas in transplantation patients. Transplant. Proc. 1, 106–112 (1969).

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Nagington, J. & Gray, J. Cyclosporin A immunosuppression, Epstein–Barr antibody, and lymphoma. Lancet 1, 536–537 (1980).

    CAS  PubMed  Google Scholar 

  107. Crawford, D. H. et al. Epstein Barr virus nuclear antigen positive lymphoma after cyclosporin A treatment in patient with renal allograft. Lancet 1, 1355–1356 (1980).

    CAS  PubMed  Google Scholar 

  108. Hanto, D. W., Sakamoto, K., Purtilo, D. T., Simmons, R. L. & Najarian, J. S. The Epstein–Barr virus in the pathogenesis of posttransplant lymphoproliferative disorders. Clinical, pathologic, and virologic correlation. Surgery 90, 204–213 (1981).

    CAS  PubMed  Google Scholar 

  109. Saemundsen, A. K. et al. Documentation of Epstein–Barr virus infection in immunodeficient patients with life-threatening lymphoproliferative diseases by Epstein–Barr virus complementary RNA/DNA and viral DNA/DNA hybridization. Cancer Res. 41, 4237–4242 (1981).

    CAS  PubMed  Google Scholar 

  110. Hanto, D. W. et al. Epstein–Barr virus (EBV) induced polyclonal and monoclonal B-cell lymphoproliferative diseases occurring after renal transplantation. Clinical, pathologic, and virologic findings and implications for therapy. Ann. Surg. 198, 356–369 (1983).

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Schubach, W. H., Hackman, R., Neiman, P. E., Miller, G. & Thomas, E. D. A monoclonal immunoblastic sarcoma in donor cells bearing Epstein–Barr virus genomes following allogeneic marrow grafting for acute lymphoblastic leukemia. Blood 60, 180–187 (1982).

    CAS  PubMed  Google Scholar 

  112. Dotti, G. et al. Lymphomas occurring late after solid-organ transplantation: influence of treatment on the clinical outcome. Transplantation 74, 1095–1102 (2002).

    PubMed  Google Scholar 

  113. Rea, D. et al. Epstein–Barr virus latent and replicative gene expression in post-transplant lymphoproliferative disorders and AIDS-related non-Hodgkin's lymphomas. French Study Group of Pathology for HIV-associated Tumors. Ann. Oncol. 5 (Suppl. 1), 113–116 (1994).

    PubMed  Google Scholar 

  114. Kanakry, J. A. & Ambinder, R. F. EBV-related lymphomas: new approaches to treatment. Curr. Treat. Opt. Oncol. 14, 224–236 (2013).

    Google Scholar 

  115. Simmons, R. L. & Najarian, J. S. Immunosuppression and malignant neoplasms. N. Engl. J. Med. 283, 934–935 (1970).

    CAS  PubMed  Google Scholar 

  116. Starzl, T. E. et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1, 583–587 (1984).

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Rooney, C. M. et al. Use of gene-modified virus-specific T lymphocytes to control Epstein–Barr-virus-related lymphoproliferation. Lancet 345, 9–13 (1995).

    CAS  PubMed  Google Scholar 

  118. Heslop, H. E. et al. 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 (1996).

    CAS  PubMed  Google Scholar 

  119. Bollard, C. M. et al. Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein–Barr virus latent membrane proteins. J. Clin. Oncol. 32, 798–808 (2014).

    CAS  PubMed  Google Scholar 

  120. Oyama, T. et al. Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients. Clin. Cancer Res. 13, 5124–5132 (2007).

    CAS  PubMed  Google Scholar 

  121. Purtilo, D. T., Cassel, C. K., Yang, J. P. & Harper, R. X-Linked recessive progressive combined variable immunodeficiency (Duncan's disease). Lancet 1, 935–940 (1975).

    CAS  PubMed  Google Scholar 

  122. Seemayer, T. A. et al. X-Linked lymphoproliferative disease: twenty-five years after the discovery. Pediatr. Res. 38, 471–478 (1995).

    CAS  PubMed  Google Scholar 

  123. Coffey, A. J. et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat. Genet. 20, 129–135 (1998).

    CAS  PubMed  Google Scholar 

  124. Nichols, K. E. et al. Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proc. Natl Acad. Sci. USA 95, 13765–13770 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Sayos, J. et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395, 462–469 (1998).

    CAS  PubMed  Google Scholar 

  126. Hislop, A. D. et al. Impaired Epstein–Barr virus-specific CD8+ T-cell function in X-linked lymphoproliferative disease is restricted to SLAM family-positive B-cell targets. Blood 116, 3249–3257 (2010).

    CAS  PubMed  Google Scholar 

  127. MacMahon, B. Epidemiology of Hodgkin's disease. Cancer Res. 26, 1189–1201 (1966).

    CAS  PubMed  Google Scholar 

  128. Correa, P. & O'Conor, G. T. Epidemiologic patterns of Hodgkin's disease. Int. J. Cancer 8, 192–201 (1971).

    CAS  PubMed  Google Scholar 

  129. Connelly, R. R. & Christine, B. W. A cohort study of cancer following infectious mononucleosis. Cancer Res. 34, 1172–1178 (1974).

    CAS  PubMed  Google Scholar 

  130. Rosdahl, N., Larsen, S. O. & Clemmesen, J. Hodgkin's disease in patients with previous infectious mononucleosis: 30 years' experience. Br. Med. J. 2, 253–256 (1974).

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Poppema, S., van Imhoff, G., Torensma, R. & Smit, J. Lymphadenopathy morphologically consistent with Hodgkin's disease associated with Epstein–Barr virus infection. Am. J. Clin. Pathol. 84, 385–390 (1985).

    CAS  PubMed  Google Scholar 

  132. Weiss, L. M., Strickler, J. G., Warnke, R. A., Purtilo, D. T. & Sklar, J. Epstein–Barr viral DNA in tissues of Hodgkin's disease. Am. J. Pathol. 129, 86–91 (1987).

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Weiss, L. M., Movahed, L. A., Warnke, R. A. & Sklar, J. Detection of Epstein–Barr viral genomes in Reed–Sternberg cells of Hodgkin's disease. N. Engl. J. Med. 320, 502–506 (1989).

    CAS  PubMed  Google Scholar 

  134. Wu, T. C. et al. Detection of EBV gene expression in Reed–Sternberg cells of Hodgkin's disease. Int. J. Cancer 46, 801–804 (1990).

    CAS  PubMed  Google Scholar 

  135. Kuppers, R. et al. Hodgkin disease: Hodgkin and Reed–Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development. Proc. Natl Acad. Sci. USA 91, 10962–10966 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Brauninger, A. et al. Molecular biology of Hodgkin's and Reed/Sternberg cells in Hodgkin's lymphoma. Int. J. Cancer 118, 1853–1861 (2006).

    PubMed  Google Scholar 

  137. Chaganti, S. et al. Epstein–Barr virus infection in vitro can rescue germinal center B cells with inactivated immunoglobulin genes. Blood 106, 4249–4252 (2005).

    CAS  PubMed  Google Scholar 

  138. Mancao, C., Altmann, M., Jungnickel, B. & Hammerschmidt, W. Rescue of “crippled” germinal center B cells from apoptosis by Epstein–Barr virus. Blood 106, 4339–4344 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Bechtel, D., Kurth, J., Unkel, C. & Kuppers, R. Transformation of BCR-deficient germinal-center B cells by EBV supports a major role of the virus in the pathogenesis of Hodgkin and posttransplantation lymphomas. Blood 106, 4345–4350 (2005).

    CAS  PubMed  Google Scholar 

  140. Pallesen, G., Hamilton-Dutoit, S. J., Rowe, M. & Young, L. S. Expression of Epstein–Barr virus latent gene products in tumour cells of Hodgkin's disease. Lancet 337, 320–322 (1991).

    CAS  PubMed  Google Scholar 

  141. Murray, P. G., Young, L. S., Rowe, M. & Crocker, J. Immunohistochemical demonstration of the Epstein–Barr virus-encoded latent membrane protein in paraffin sections of Hodgkin's disease. J. Pathol. 166, 1–5 (1992).

    CAS  PubMed  Google Scholar 

  142. Deacon, E. M. et al. Epstein–Barr virus and Hodgkin's disease: transcriptional analysis of virus latency in the malignant cells. J. Exp. Med. 177, 339–349 (1993).

    CAS  PubMed  Google Scholar 

  143. Murray, P. G., Constandinou, C. M., Crocker, J., Young, L. S. & Ambinder, R. F. Analysis of major histocompatibility complex class I, TAP expression, and LMP2 epitope sequence in Epstein–Barr virus-positive Hodgkin's disease. Blood 92, 2477–2483 (1998).

    CAS  PubMed  Google Scholar 

  144. Alber, G. et al. Molecular mimicry of the antigen receptor signalling motif by transmembrane proteins of the Epstein–Barr virus and the bovine leukaemia virus. Curr. Biol. 3, 333–339 (1993).

    CAS  PubMed  Google Scholar 

  145. Mosialos, G. et al. The Epstein–Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80, 389–399 (1995).

    CAS  PubMed  Google Scholar 

  146. Hjalgrim, H. et al. Infectious mononucleosis, childhood social environment, and risk of Hodgkin lymphoma. Cancer Res. 67, 2382–2388 (2007).

    CAS  PubMed  Google Scholar 

  147. Hjalgrim, H. et al. HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma. Proc. Natl Acad. Sci. USA 107, 6400–6405 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Diepstra, A. et al. Association with HLA class I in Epstein–Barr-virus-positive and with HLA class III in Epstein–Barr-virus-negative Hodgkin's lymphoma. Lancet 365, 2216–2224 (2005).

    CAS  PubMed  Google Scholar 

  149. Doll, D. C. & List, A. F. Burkitt's lymphoma in a homosexual. Lancet 1, 1026–1027 (1982).

    CAS  PubMed  Google Scholar 

  150. Ziegler, J. L. et al. Outbreak of Burkitt's-like lymphoma in homosexual men. Lancet 2, 631–633 (1982).

    CAS  PubMed  Google Scholar 

  151. Chaganti, R. S. et al. Specific translocations characterize Burkitt's-like lymphoma of homosexual men with the acquired immunodeficiency syndrome. Blood 61, 1265–1268 (1983).

    CAS  PubMed  Google Scholar 

  152. Moir, S. & Fauci, A. S. Insights into B cells and HIV-specific B-cell responses in HIV-infected individuals. Immunol. Rev. 254, 207–224 (2013).

    PubMed  Google Scholar 

  153. Haas, A., Zimmermann, K. & Oxenius, A. Antigen-dependent and -independent mechanisms of T and B cell hyperactivation during chronic HIV-1 infection. J. Virol. 85, 12102–12113 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  154. Biggar, R. J. et al. Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood 108, 3786–3791 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  155. Jones, J. F. et al. T-Cell lymphomas containing Epstein–Barr viral DNA in patients with chronic Epstein–Barr virus infections. N. Engl. J. Med. 318, 733–741 (1988).

    CAS  PubMed  Google Scholar 

  156. Kikuta, H. et al. Epstein–Barr virus genome-positive T lymphocytes in a boy with chronic active EBV infection associated with Kawasaki-like disease. Nature 333, 455–457 (1988).

    CAS  PubMed  Google Scholar 

  157. Harabuchi, Y. et al. Epstein–Barr virus in nasal T-cell lymphomas in patients with lethal midline granuloma. Lancet 335, 128–130 (1990).

    CAS  PubMed  Google Scholar 

  158. Cohen, J. I. Optimal treatment for chronic active Epstein–Barr virus disease. Pediatr. Transplant. 13, 393–396 (2009).

    PubMed Central  PubMed  Google Scholar 

  159. Au, W. Y. et al. Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project. Blood 113, 3931–3937 (2009).

    CAS  PubMed  Google Scholar 

  160. Chiang, A. K., Tao, Q., Srivastava, G. & Ho, F. C. 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 (1996).

    CAS  PubMed  Google Scholar 

  161. Coleman, C. B. et al. Epstein–Barr virus type 2 latently infects T cells, inducing an atypical activation characterized by expression of lymphotactic cytokines. J. Virol. 89, 2301–2312 (2015).

    PubMed  Google Scholar 

  162. Ng, S. B. et al. Activated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling. J. Pathol. 223, 496–510 (2011).

    CAS  PubMed  Google Scholar 

  163. de Schryver, A. et al. Epstein–Barr virus-associated antibody patterns in carcinoma of the post-nasal space. Clin. Exp. Immunol. 5, 443–459 (1969).

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Henle, W. et al. Antibodies to Epstein–Barr virus in nasopharyngeal carcinoma, other head and neck neoplasms, and control groups. J. Natl Cancer Inst. 44, 225–231 (1970).

    CAS  PubMed  Google Scholar 

  165. Henle, W., Ho, J. H., Henle, G., Chau, J. C. & Kwan, H. C. Nasopharyngeal carcinoma: significance of changes in Epstein–Barr virus-related antibody patterns following therapy. Int. J. Cancer 20, 663–672 (1977).

    CAS  PubMed  Google Scholar 

  166. Zeng, Y. et al. Prospective studies on nasopharyngeal carcinoma in Epstein–Barr virus IgA/VCA antibody-positive persons in Wuzhou City, China. Int. J. Cancer 36, 545–547 (1985).

    CAS  PubMed  Google Scholar 

  167. Mutirangura, A. et al. Epstein–Barr viral DNA in serum of patients with nasopharyngeal carcinoma. Clin. Cancer Res. 4, 665–669 (1998).

    CAS  PubMed  Google Scholar 

  168. Lo, Y. M. et al. Quantitative and temporal correlation between circulating cell-free Epstein–Barr virus DNA and tumor recurrence in nasopharyngeal carcinoma. Cancer Res. 59, 5452–5455 (1999).

    CAS  PubMed  Google Scholar 

  169. Wolf, H., zur Hausen, H. & Becker, V. EB viral genomes in epithelial nasopharyngeal carcinoma cells. Nat. New Biol. 244, 245–247 (1973).

    CAS  PubMed  Google Scholar 

  170. Pathmanathan, R., Prasad, U., Sadler, R., Flynn, K. & Raab-Traub, N. Clonal proliferations of cells infected with Epstein–Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N. Engl. J. Med. 333, 693–698 (1995).

    CAS  PubMed  Google Scholar 

  171. Fahraeus, R. et al. Expression of Epstein–Barr virus-encoded proteins in nasopharyngeal carcinoma. Int. J. Cancer 42, 329–338 (1988).

    CAS  PubMed  Google Scholar 

  172. Brooks, L., Yao, Q. Y., Rickinson, A. B. & Young, L. S. Epstein–Barr virus latent gene transcription in nasopharyngeal carcinoma cells: coexpression of EBNA1, LMP1, and LMP2 transcripts. J. Virol. 66, 2689–2697 (1992).

    CAS  PubMed Central  PubMed  Google Scholar 

  173. Busson, P. et al. Consistent transcription of the Epstein–Barr virus LMP2 gene in nasopharyngeal carcinoma. J. Virol. 66, 3257–3262 (1992).

    CAS  PubMed Central  PubMed  Google Scholar 

  174. Niedobitek, G. et al. Epstein–Barr virus and carcinomas: undifferentiated carcinomas but not squamous cell carcinomas of the nasopharynx are regularly associated with the virus. J. Pathol. 165, 17–24 (1991).

    CAS  PubMed  Google Scholar 

  175. Sheen, T. S., Tsai, C. C., Ko, J. Y., Chang, Y. L. & Hsu, M. M. Undifferentiated carcinoma of the major salivary glands. Cancer 80, 357–363 (1997).

    CAS  PubMed  Google Scholar 

  176. Lo, K. W., Chung, G. T. & To, K. F. Deciphering the molecular genetic basis of NPC through molecular, cytogenetic, and epigenetic approaches. Semin. Cancer Biol. 22, 79–86 (2012).

    CAS  PubMed  Google Scholar 

  177. Jia, W. H. & Qin, H. D. Non-viral environmental risk factors for nasopharyngeal carcinoma: a systematic review. Semin. Cancer Biol. 22, 117–126 (2012).

    PubMed  Google Scholar 

  178. Young, L. S. & Rickinson, A. B. Epstein–Barr virus: 40 years on. Nat. Rev. Cancer 4, 757–768 (2004).

    CAS  PubMed  Google Scholar 

  179. Lin, D. C. et al. The genomic landscape of nasopharyngeal carcinoma. Nat. Genet. 46, 866–871 (2014).

    CAS  PubMed  Google Scholar 

  180. Shibata, D. & Weiss, L. M. Epstein–Barr virus-associated gastric adenocarcinoma. Am. J. Pathol. 140, 769–774 (1992).

    CAS  PubMed Central  PubMed  Google Scholar 

  181. Global Cancer Observatory. Estimated cancer incidence, mortality and prevalence worldwide in 2012. Globocan 2012 Cancer Fact Sheet: Stomach cancer. http://globocan.iarc.fr/old/FactSheets/cancers/stomach-new.asp (2012).

  182. Lee, J. H. et al. Clinicopathological and molecular characteristics of Epstein–Barr virus-associated gastric carcinoma: a meta-analysis. J. Gastroenterol. Hepatol. 24, 354–365 (2009).

    PubMed  Google Scholar 

  183. Murphy, G., Pfeiffer, R., Camargo, M. C. & Rabkin, C. S. Meta-analysis shows that prevalence of Epstein–Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology 137, 824–833 (2009).

    PubMed  Google Scholar 

  184. Lee, H. S., Chang, M. S., Yang, H. K., Lee, B. L. & Kim, W. H. Epstein–Barr virus-positive gastric carcinoma has a distinct protein expression profile in comparison with Epstein−Barr virus-negative carcinoma. Clin. Cancer Res. 10, 1698–1705 (2004).

    CAS  PubMed  Google Scholar 

  185. Schneider, B. G. et al. Loss of p16/CDKN2A tumor suppressor protein in gastric adenocarcinoma is associated with Epstein–Barr virus and anatomic location in the body of the stomach. Hum. Pathol. 31, 45–50 (2000).

    CAS  PubMed  Google Scholar 

  186. Ushiku, T. et al. p73 gene promoter methylation in Epstein–Barr virus-associated gastric carcinoma. Int. J. Cancer 120, 60–66 (2007).

    CAS  PubMed  Google Scholar 

  187. van Rees, B. P. et al. Different pattern of allelic loss in Epstein–Barr virus-positive gastric cancer with emphasis on the p53 tumor suppressor pathway. Am. J. Pathol. 161, 1207–1213 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  188. Wang, K. et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat. Genet. 46, 573–582 (2014).

    CAS  PubMed  Google Scholar 

  189. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014).

  190. zur Hausen, A. et al. Epstein–Barr virus in gastric carcinomas and gastric stump carcinomas: a late event in gastric carcinogenesis. J. Clin. Pathol. 57, 487–491 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  191. Corvalan, A. et al. Association of a distinctive strain of Epstein–Barr virus with gastric cancer. Int. J. Cancer 118, 1736–1742 (2006).

    CAS  PubMed  Google Scholar 

  192. Muhe, J. & Wang, F. Non-human primate lymphocryptoviruses: past, present, and future. Curr. Top. Microbiol. Immunol. 391, 385–405 (2015).

    CAS  PubMed  Google Scholar 

  193. Miettinen, M. Smooth muscle tumors of soft tissue and non-uterine viscera: biology and prognosis. Mod. Pathol. 27 (Suppl. 1), 17–29 (2014).

    Google Scholar 

  194. Fernandez-Menendez, S., Fernandez-Moran, M., Fernandez-Vega, I., Perez-Alvarez, A. & Villafani-Echazu, J. Epstein–Barr virus and multiple sclerosis. From evidence to therapeutic strategies. J. Neurol. Sci. 361, 213–219 (2016).

    CAS  PubMed  Google Scholar 

  195. Imai, S., Nishikawa, J. & Takada, K. Cell-to-cell contact as an efficient mode of Epstein–Barr virus infection of diverse human epithelial cells. J. Virol. 72, 4371–4378 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  196. Shannon-Lowe, C. & Rowe, M. Epstein–Barr virus infection of polarized epithelial cells via the basolateral surface by memory B cell-mediated transfer infection. PLoS Pathog. 7, e1001338 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  197. Ni, C. et al. In-cell infection: a novel pathway for Epstein–Barr virus infection mediated by cell-in-cell structures. Cell Res. 25, 785–800 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  198. Kanda, T., Furuse, Y., Oshitani, H. & Kiyono, T. Highly efficient CRISPR/Cas9-mediated cloning and functional characterization of gastric cancer-derived Epstein–Barr virus strains. J. Virol. 90, 4383–4393 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  199. Nakatsuka, S. et al. Pyothorax-associated lymphoma: a review of 106 cases. J. Clin. Oncol. 20, 4255–4260 (2002).

    PubMed  Google Scholar 

  200. Dojcinov, S. D., Venkataraman, G., Raffeld, M., Pittaluga, S. & Jaffe, E. S. EBV positive mucocutaneous ulcer—a study of 26 cases associated with various sources of immunosuppression. Am. J. Surg. Pathol. 34, 405–417 (2010).

    PubMed Central  PubMed  Google Scholar 

  201. Zhang, G. et al. Circulating Epstein–Barr virus microRNAs miR-BART7 and miR-BART13 as biomarkers for nasopharyngeal carcinoma diagnosis and treatment. Int. J. Cancer 136, E301–E312 (2015).

    CAS  PubMed  Google Scholar 

  202. Yang, X. et al. Epigenetic markers for noninvasive early detection of nasopharyngeal carcinoma by methylation-sensitive high resolution melting. Int. J. Cancer 136, E127–E135 (2015).

    CAS  PubMed  Google Scholar 

  203. Wildeman, M. A. et al. Cytolytic virus activation therapy for Epstein–Barr virus-driven tumors. Clin. Cancer Res. 18, 5061–5070 (2012).

    CAS  PubMed  Google Scholar 

  204. Li, J. H. et al. Efficacy of targeted FasL in nasopharyngeal carcinoma. Mol. Ther. 8, 964–973 (2003).

    CAS  PubMed  Google Scholar 

  205. Lee, E. K. et al. Small molecule inhibition of Epstein–Barr virus nuclear antigen-1 DNA binding activity interferes with replication and persistence of the viral genome. Antiviral Res. 104, 73–83 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  206. Gianti, E., Messick, T. E., Lieberman, P. M. & Zauhar, R. J. Computational analysis of EBNA1 “druggability” suggests novel insights for Epstein–Barr virus inhibitor design. J. Comput. Aided Mol. Des. 30, 285–303 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  207. Taylor, G. S. et al. A recombinant modified vaccinia ankara vaccine encoding Epstein–Barr virus (EBV) target antigens: a phase I trial in UK patients with EBV-positive cancer. Clin. Cancer Res. 20, 5009–5022 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  208. Smith, C. et al. Effective treatment of metastatic forms of Epstein–Barr virus-associated nasopharyngeal carcinoma with a novel adenovirus-based adoptive immunotherapy. Cancer Res. 72, 1116–1125 (2012).

    CAS  PubMed  Google Scholar 

  209. Barton, E. S. et al. Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447, 326–329 (2007).

    CAS  PubMed  Google Scholar 

  210. Zimber, U. et al. Geographical prevalence of two types of Epstein–Barr virus. Virology 154, 56–66 (1986).

    CAS  PubMed  Google Scholar 

  211. Rickinson, A. B., Young, L. S. & Rowe, M. Influence of the Epstein–Barr virus nuclear antigen EBNA 2 on the growth phenotype of virus-transformed B cells. J. Virol. 61, 1310–1317 (1987).

    CAS  PubMed Central  PubMed  Google Scholar 

  212. Yates, J. L., Warren, N. & Sugden, B. Stable replication of plasmids derived from Epstein–Barr virus in various mammalian cells. Nature 313, 812–815 (1985).

    CAS  PubMed  Google Scholar 

  213. Wilson, J. B., Bell, J. L. & Levine, A. J. Expression of Epstein–Barr virus nuclear antigen-1 induces B cell neoplasia in transgenic mice. EMBO J. 15, 3117–3126 (1996).

    CAS  PubMed Central  PubMed  Google Scholar 

  214. Gruhne, B. et al. The Epstein–Barr virus nuclear antigen-1 promotes genomic instability via induction of reactive oxygen species. Proc. Natl Acad. Sci. USA 106, 2313–2318 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Rabson, M., Gradoville, L., Heston, L. & Miller, G. Non-immortalizing P3J-HR-1 Epstein–Barr virus: a deletion mutant of its transforming parent, Jijoye. J. Virol. 44, 834–844 (1982).

    CAS  PubMed Central  PubMed  Google Scholar 

  216. Sakai, T. et al. Functional replacement of the intracellular region of the Notch1 receptor by Epstein–Barr virus nuclear antigen 2. J. Virol. 72, 6034–6039 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  217. Tomkinson, B., Robertson, E. & Kieff, E. Epstein–Barr virus nuclear proteins EBNA-3A and EBNA-3C are essential for B-lymphocyte growth transformation. J. Virol. 67, 2014–2025 (1993).

    CAS  PubMed Central  PubMed  Google Scholar 

  218. Parker, G. A. et al. Epstein–Barr virus nuclear antigen (EBNA)3C is an immortalizing oncoprotein with similar properties to adenovirus E1A and papillomavirus E7. Oncogene 13, 2541–2549 (1996).

    CAS  PubMed  Google Scholar 

  219. White, R. E. et al. EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors. J. Clin. Invest. 122, 1487–1502 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  220. Allan, G. J., Inman, G. J., Parker, B. D., Rowe, D. T. & Farrell, P. J. Cell growth effects of Epstein–Barr virus leader protein. J. Gen. Virol. 73, 1547–1551 (1992).

    CAS  PubMed  Google Scholar 

  221. Wang, D., Liebowitz, D. & Kieff, E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell 43, 831–840 (1985).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Dawson, C. W., Port, R. J. & Young, L. S. The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). Semin. Cancer Biol. 22, 144–153 (2012).

    CAS  PubMed  Google Scholar 

  224. Longnecker, R. & Kieff, E. A second Epstein–Barr virus membrane protein (LMP2) is expressed in latent infection and colocalizes with LMP1. J. Virol. 64, 2319–2326 (1990).

    CAS  PubMed Central  PubMed  Google Scholar 

  225. Pearson, G. R. et al. Identification of an Epstein–Barr virus early gene encoding a second component of the restricted early antigen complex. Virology 160, 151–161 (1987).

    CAS  PubMed  Google Scholar 

  226. Henderson, S. et al. Epstein–Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death. Proc. Natl Acad. Sci. USA 90, 8479–8483 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Watanabe, A. et al. Epstein–Barr virus-encoded Bcl-2 homologue functions as a survival factor in Wp-restricted Burkitt lymphoma cell line P3HR-1. J. Virol. 84, 2893–2901 (2010).

    CAS  PubMed  Google Scholar 

  228. Wei, M. X. & Ooka, T. A transforming function of the BARF1 gene encoded by Epstein–Barr virus. EMBO J. 8, 2897–2903 (1989).

    CAS  PubMed Central  PubMed  Google Scholar 

  229. Wei, M. X., Moulin, J. C., Decaussin, G., Berger, F. & Ooka, T. Expression and tumorigenicity of the Epstein–Barr virus BARF1 gene in human Louckes B-lymphocyte cell line. Cancer Res. 54, 1843–1848 (1994).

    CAS  PubMed  Google Scholar 

  230. Zhang, C. X., Decaussin, G., Daillie, J. & Ooka, T. Altered expression of two Epstein–Barr virus early genes localized in BamHI-A in nonproducer Raji cells. J. Virol. 62, 1862–1869 (1988).

    CAS  PubMed Central  PubMed  Google Scholar 

  231. Seto, E. et al. Epstein–Barr virus (EBV)-encoded BARF1 gene is expressed in nasopharyngeal carcinoma and EBV-associated gastric carcinoma tissues in the absence of lytic gene expression. J. Med. Virol. 76, 82–88 (2005).

    CAS  PubMed  Google Scholar 

  232. Pfeffer, S. et al. Identification of virus-encoded microRNAs. Science 304, 734–736 (2004).

    CAS  PubMed  Google Scholar 

  233. Kozomara, A. & Griffiths-Jones, S. miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 42, D68–D73 (2014).

    CAS  PubMed  Google Scholar 

  234. Marquitz, A. R. & Raab-Traub, N. The role of miRNAs and EBV BARTs in NPC. Semin. Cancer Biol. 22, 166–172 (2012).

    CAS  PubMed  Google Scholar 

  235. Vereide, D. T. et al. Epstein–Barr virus maintains lymphomas via its miRNAs. Oncogene 33, 1258–1264 (2014).

    CAS  PubMed  Google Scholar 

  236. Shinozaki-Ushiku, A. et al. Profiling of virus-encoded microRNAs in Epstein–Barr virus-associated gastric carcinoma and their roles in gastric carcinogenesis. J. Virol. 89, 5581–5591 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  237. Kang, D., Skalsky, R. L. & Cullen, B. R. EBV BART microRNAs target multiple pro-apoptotic cellular genes to promote epithelial cell survival. PLoS Pathog. 11, e1004979 (2015).

    PubMed Central  PubMed  Google Scholar 

  238. Lei, T. et al. Targeting of DICE1 tumor suppressor by Epstein–Barr virus-encoded miR-BART3* microRNA in nasopharyngeal carcinoma. Int. J. Cancer 133, 79–87 (2013).

    CAS  PubMed  Google Scholar 

  239. Hsu, C. Y. et al. The Epstein–Barr virus-encoded microRNA MiR-BART9 promotes tumor metastasis by targeting E-cadherin in nasopharyngeal carcinoma. PLoS Pathog. 10, e1003974 (2014).

    PubMed Central  PubMed  Google Scholar 

  240. Kanda, T. et al. Clustered microRNAs of the Epstein–Barr virus cooperatively downregulate an epithelial cell-specific metastasis suppressor. J. Virol. 89, 2684–2697 (2015).

    PubMed  Google Scholar 

  241. Qiu, J., Smith, P., Leahy, L. & Thorley-Lawson, D. A. The Epstein–Barr virus encoded BART miRNAs potentiate tumor growth in vivo. PLoS Pathog. 11, e1004561 (2015).

    PubMed Central  PubMed  Google Scholar 

  242. Cai, L. et al. Epstein–Barr virus-encoded microRNA BART1 induces tumour metastasis by regulating PTEN-dependent pathways in nasopharyngeal carcinoma. Nature Commun. 6, 7353 (2015).

    Google Scholar 

  243. Wong, A. M., Kong, K. L., Tsang, J. W., Kwong, D. L. & Guan, X. Y. Profiling of Epstein–Barr virus-encoded microRNAs in nasopharyngeal carcinoma reveals potential biomarkers and oncomirs. Cancer 118, 698–710 (2012).

    CAS  PubMed  Google Scholar 

  244. Feederle, R. et al. The members of an Epstein–Barr virus microRNA cluster cooperate to transform B lymphocytes. J. Virol. 85, 9801–9810 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  245. Rymo, L. Identification of transcribed regions of Epstein–Barr virus DNA in Burkitt lymphoma-derived cells. J. Virol. 32, 8–18 (1979).

    CAS  PubMed Central  PubMed  Google Scholar 

  246. Glickman, J. N., Howe, J. G. & Steitz, J. A. Structural analyses of EBER1 and EBER2 ribonucleoprotein particles present in Epstein–Barr virus-infected cells. J. Virol. 62, 902–911 (1988).

    CAS  PubMed Central  PubMed  Google Scholar 

  247. Takada, K. Role of EBER and BARF1 in nasopharyngeal carcinoma (NPC) tumorigenesis. Semin. Cancer Biol. 22, 162–165 (2012).

    CAS  PubMed  Google Scholar 

  248. Fixman, E. D., Hayward, G. S. & Hayward, S. D. Trans-acting requirements for replication of Epstein–Barr virus ori-Lyt. J. Virol. 66, 5030–5039 (1992).

    CAS  PubMed Central  PubMed  Google Scholar 

  249. Schepers, A., Pich, D. & Hammerschmidt, W. Activation of oriLyt, the lytic origin of DNA replication of Epstein–Barr virus, by BZLF1. Virology 220, 367–376 (1996).

    CAS  PubMed  Google Scholar 

  250. Zhang, Q. et al. Functional and physical interactions between the Epstein–Barr virus (EBV) proteins BZLF1 and BMRF1: effects on EBV transcription and lytic replication. J. Virol. 70, 5131–5142 (1996).

    CAS  PubMed Central  PubMed  Google Scholar 

  251. Gao, Z. et al. The Epstein–Barr virus lytic transactivator Zta interacts with the helicase-primase replication proteins. J. Virol. 72, 8559–8567 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  252. Wen, W. et al. Epstein–Barr virus BZLF1 gene, a switch from latency to lytic infection, is expressed as an immediate-early gene after primary infection of B lymphocytes. J. Virol. 81, 1037–1042 (2007).

    CAS  PubMed  Google Scholar 

  253. Shannon-Lowe, C. et al. Features distinguishing Epstein–Barr virus infections of epithelial cells and B cells: viral genome expression, genome maintenance, and genome amplification. J. Virol. 83, 7749–7760 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  254. Bhende, P. M., Seaman, W. T., Delecluse, H. J. & Kenney, S. C. The EBV lytic switch protein, Z, preferentially binds to and activates the methylated viral genome. Nat. Genet. 36, 1099–1104 (2004).

    CAS  PubMed  Google Scholar 

  255. Ma, S. D. et al. An Epstein–Barr virus (EBV) mutant with enhanced BZLF1 expression causes lymphomas with abortive lytic EBV infection in a humanized mouse model. J. Virol. 86, 7976–7987 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  256. Hislop, A. D. et al. A CD8+ T cell immune evasion protein specific to Epstein–Barr virus and its close relatives in Old World primates. J. Exp. Med. 204, 1863–1873 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  257. Zuo, J. et al. The Epstein–Barr virus G-protein-coupled receptor contributes to immune evasion by targeting MHC class I molecules for degradation. PLoS Pathog. 5, e1000255 (2009).

    PubMed Central  PubMed  Google Scholar 

  258. Rowe, M. et al. Host shutoff during productive Epstein–Barr virus infection is mediated by BGLF5 and may contribute to immune evasion. Proc. Natl Acad. Sci. USA 104, 3366–3371 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  259. Hong, G. K. et al. Epstein–Barr virus lytic infection contributes to lymphoproliferative disease in a SCID mouse model. J. Virol. 79, 13993–14003 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  260. Ma, S. D. et al. A new model of Epstein–Barr virus infection reveals an important role for early lytic viral protein expression in the development of lymphomas. J. Virol. 85, 165–177 (2011).

    CAS  PubMed  Google Scholar 

  261. Sato, Y. et al. Degradation of phosphorylated p53 by viral protein-ECS E3 ligase complex. PLoS Pathog. 5, e1000530 (2009).

    PubMed Central  PubMed  Google Scholar 

  262. Chang, Y. H. et al. Epstein–Barr virus BGLF4 kinase retards cellular S-phase progression and induces chromosomal abnormality. PLoS ONE 7, e39217 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  263. Wu, C. C. et al. Epstein–Barr virus DNase (BGLF5) induces genomic instability in human epithelial cells. Nucleic Acids Res. 38, 1932–1949 (2010).

    CAS  PubMed  Google Scholar 

  264. Lin, Z. et al. Quantitative and qualitative RNA–Seq-based evaluation of Epstein–Barr virus transcription in type I latency Burkitt's lymphoma cells. J. Virol. 84, 13053–13058 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  265. Young, L. S. & Murray, P. G. Epstein–Barr virus and oncogenesis: from latent genes to tumours. Oncogene 22, 5108–5121 (2003).

    CAS  PubMed  Google Scholar 

  266. Lo, K. W. & Huang, D. P. Genetic and epigenetic changes in nasopharyngeal carcinoma. Semin. Cancer Biol. 12, 451–462 (2002).

    CAS  PubMed  Google Scholar 

  267. Tsang, C. M. et al. Cyclin D1 overexpression supports stable EBV infection in nasopharyngeal epithelial cells. Proc. Natl Acad. Sci. USA 109, E3473–E3482 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  268. Sheu, L. F. et al. Analysis of bcl-2 expression in normal, inflamed, dysplastic nasopharyngeal epithelia, and nasopharyngeal carcinoma: association with p53 expression. Hum. Pathol. 28, 556–562 (1997).

    CAS  PubMed  Google Scholar 

  269. Chang, J. T. et al. Telomerase activity is frequently found in metaplastic and malignant human nasopharyngeal tissues. Br. J. Cancer 82, 1946–1951 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  270. Hao, D. et al. Evaluation of E-cadherin, beta-catenin and vimentin protein expression using quantitative immunohistochemistry in nasopharyngeal carcinoma patients. Clin. Invest. Med. 37, E320–E330 (2014).

    PubMed  Google Scholar 

  271. Li, L., Zhang, Y., Guo, B. B., Chan, F. K. & Tao, Q. Oncogenic induction of cellular high CpG methylation by Epstein–Barr virus in malignant epithelial cells. Chin. J. Cancer 33, 604–608 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to A. Bell for help with revisions to the figures. L.S.Y. has been supported by Cancer Research UK. L.F.Y. is supported by High Impact Research Grant UM.C/625/1/HIR/MOHE/DENT/23 from the University of Malaya. P.G.M. is supported by a Bloodwise Programme Grant.

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Young, L., Yap, L. & Murray, P. Epstein–Barr virus: more than 50 years old and still providing surprises. Nat Rev Cancer 16, 789–802 (2016). https://doi.org/10.1038/nrc.2016.92

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