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Original

Regulation and dysregulation of Epstein–Barr virus latency: Implications for the development of autoimmune diseases

, &
Pages 298-328 | Received 24 Aug 2007, Accepted 03 Mar 2008, Published online: 07 Jul 2009

References

  • Burkitt D. A sarcoma involving the jaws in African children. Br J Surg 1958; 45: 218–223
  • Burkitt D. A children's cancer dependent upon climatic factors. Nature 1962; 194: 232–234
  • Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet 1964; 1: 702–703
  • Pulvertaft RJ. Cytology of Burkitt's tumor (African lymphoma). Lancet 1964; 1: 238–240
  • Henle G, Henle W, Diehl V. Relation of Burkitt's tumor-associated herpes-type virus to infectious mononucleosis. Proc Natl Acad Sci USA 1968; 59: 94–101
  • Thompson MP, Kurzrock R. Epstein–Barr virus and cancer. Clin Cancer Res 2004; 10: 803–821
  • Niller HH, Wolf H, Minarovits J. Epstein–Barr virus. Latency strategies of herpesviruses, J Minarovits, E Gonczol, T Valyi-Nagy. Springer, New York 2007; 154–191
  • Shannon-Lowe CD, Neuhierl B, Baldwin G, Rickinson AB, Delecluse HJ. Resting B cells as a transfer vehicle for Epstein–Barr virus infection of epithelial cells. Proc Natl Acad Sci USA 2006; 103: 7065–7070
  • Wolf H, Haus M, Wilmes E. Persistence of Epstein–Barr virus in the parotid gland. J Virol 1984; 51: 795–798
  • Borza CM, Hutt-Fletcher LM. Alternate replication in B cells and epithelial cells switches tropism of Epstein–Barr virus. Nat Med 2002; 8: 594–599
  • Thorley-Lawson DA, Gross A. Persistence of the Epstein–Barr virus and the origins of associated lymphomas. N Engl J Med 2004; 350: 1328–1337
  • Souza TA, Stollar BD, Sullivan JL, Luzuriaga K, Thorley-Lawson DA. Peripheral B cells latently infected with Epstein–Barr virus display molecular hallmarks of classical antigen-selected memory B cells. Proc Natl Acad Sci USA 2005; 102: 18093–18098
  • Kurth J, Spieker T, Wustrow J, et al. EBV-infected B cells in infectious mononucleosis: Viral strategies for spreading in the B cell compartment and establishing latency. Immunity 2000; 13: 485–495
  • Kurth J, Hansmann ML, 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 2003; 100: 4730–4735
  • Ehlin-Henriksson B, Gordon J, Klein G. B-lymphocyte subpopulations are equally susceptible to Epstein–Barr virus infection, irrespective of immunoglobulin isotype expression. Immunology 2003; 108: 427–430
  • Crawford DH. Biology and disease associations of Epstein–Barr virus. Philos Trans R Soc Lond B Biol Sci 2001; 356: 461–473
  • Hochberg D, Souza T, Catalina M, Sullivan JL, Luzuriaga K, Thorley-Lawson DA. Acute infection with Epstein–Barr virus targets and overwhelms the peripheral memory B-cell compartment with resting, latently infected cells. J Virol 2004; 78: 5194–5204
  • Tierney RJ, Steven N, Young LS, Rickinson AB. Epstein–Barr virus latency in blood mononuclear cells: Analysis of viral gene transcription during primary infection and in the carrier state. J Virol 1994; 68: 7374–7385
  • Tosato G, Magrath I, Koski I, Dooley N, Blaese M. Activation of suppressor T cells during Epstein–Barr-virus-induced infectious mononucleosis. N Engl J Med 1979; 301: 1133–1137
  • Moss DJ, Burrows SR, Silins SL, Misko I, Khanna R. The immunology of Epstein–Barr virus infection. Philos Trans R Soc Lond B Biol Sci 2001; 356: 475–488
  • Silins SL, Sherritt MA, Silleri JM, et al. Asymptomatic primary Epstein–Barr virus infection occurs in the absence of blood T-cell repertoire perturbations despite high levels of systemic viral load. Blood 2001; 98: 3739–3744
  • Niedobitek G, Agathanggelou A, Herbst H, Whitehead L, Wright DH, Young LS. Epstein–Barr virus (EBV) infection in infectious mononucleosis: Virus latency, replication and phenotype of EBV-infected cells. J Pathol 1997; 182: 151–159
  • Klein E, Kis LL, Klein G. Epstein–Barr virus infection in humans: From harmless to life endangering virus-lymphocyte interactions. Oncogene 2007; 26: 1297–1305
  • Niller HH, Glaser G, Knuchel R, Wolf H. Nucleoprotein complexes and DNA 5′-ends at oriP of Epstein–Barr virus. J Biol Chem 1995; 270: 12864–12868
  • Vogel M, Wittmann K, Endl E, et al. Plasmid maintenance assay based on green fluorescent protein and FACS of mammalian cells. Biotechniques 1998; 24: 540–544
  • Yates JL, Camiolo SM, Bashaw JM. The minimal replicator of Epstein–Barr virus oriP. J Virol 2000; 74: 4512–4522
  • Deng Z, Atanasiu C, Zhao K, et al. Inhibition of Epstein–Barr virus OriP function by tankyrase, a telomere-associated poly-ADP ribose polymerase that binds and modifies EBNA1. J Virol 2005; 79: 4640–4650
  • Atanasiu C, Deng Z, Wiedmer A, Norseen J, Lieberman PM. ORC binding to TRF2 stimulates OriP replication. EMBO Rep 2006; 7: 716–721
  • Sixbey JW, Lemon SM, Pagano JS. A second site for Epstein–Barr virus shedding: The uterine cervix. Lancet 1986; 2: 1122–1124
  • Walling DM, Ray AJ, Nichols JE, Flaitz CM, Nichols CM. Epstein–Barr virus infection of Langerhans cell precursors as a mechanism of oral epithelial entry, persistence, and reactivation. J Virol 2007; 81: 7249–7268
  • Laichalk LL, Thorley-Lawson DA. Terminal differentiation into plasma cells initiates the replicative cycle of Epstein–Barr virus in vivo. J Virol 2005; 79: 1296–1307
  • Crawford DH, Ando I. EB virus induction is associated with B-cell maturation. Immunology 1986; 59: 405–409
  • Seibl R, Motz M, Wolf H. Strain-specific transcription and translation of the BamHI Z area of Epstein–Barr virus. J Virol 1986; 60: 902–909
  • Grogan E, Jenson H, Countryman J, Heston L, Gradoville L, Miller G. Transfection of a rearranged viral DNA fragment, WZhet, stably converts latent Epstein–Barr viral infection to productive infection in lymphoid cells. Proc Natl Acad Sci USA 1987; 84: 1332–1336
  • Countryman J, Jenson H, Seibl R, Wolf H, Miller G. Polymorphic proteins encoded within BZLF1 of defective and standard Epstein–Barr viruses disrupt latency. J Virol 1987; 61: 3672–3679
  • Hardwick JM, Lieberman PM, Hayward SD. A new Epstein–Barr virus transactivator, R, induces expression of a cytoplasmic early antigen. J Virol 1988; 62: 2274–2284
  • Marschall M, Leser U, Seibl R, Wolf H. Identification of proteins encoded by Epstein–Barr virus trans-activator genes. J Virol 1989; 63: 938–942
  • Sinclair AJ, Brimmell M, Shanahan F, Farrell PJ. Pathways of activation of the Epstein–Barr virus productive cycle. J Virol 1991; 65: 2237–2244
  • Chan AT, Tao Q, Robertson KD, et al. Azacitidine induces demethylation of the Epstein–Barr virus genome in tumors. J Clin Oncol 2004; 22: 1373–1381
  • Amon W, Farrell PJ. Reactivation of Epstein–Barr virus from latency. Rev Med Virol 2005; 15: 149–156
  • Feng WH, Kraus RJ, Dickerson SJ, Lim HJ, Jones RJ, Yu X, Mertz JE, Kenney SC. ZEB1 and c-Jun levels contribute to the establishment of highly lytic Epstein-Barr virus injection in gastric AGS cells. J Virol 2007; 81: 10113–10122
  • Feng WH, Kenney SC. Valproic acid enhances the efficacy of chemotherapy in EBV-positive tumors by increasing lytic viral gene expression. Cancer Res 2006; 66: 8762–8769
  • Wang F, Gregory C, Sample C, et al. Epstein–Barr virus latent membrane protein (LMP1) and nuclear proteins 2 and 3C are effectors of phenotypic changes in B lymphocytes: EBNA-2 and LMP1 cooperatively induce CD23. J Virol 1990; 64: 2309–2318
  • Cheung ST, Huang DP, Hui AB, et al. Nasopharyngeal carcinoma cell line (C666-1) consistently harbouring Epstein–Barr virus. Int J Cancer 1999; 83: 121–126
  • Salamon D, Takacs M, Ujvari D, et al. Protein–DNA binding and CpG methylation at nucleotide resolution of latency-associated promoters Qp, Cp, and LMP1p of Epstein–Barr virus. J Virol 2001; 75: 2584–2596
  • Niller HH, Salamon D, Banati F, Schwarzmann F, Wolf H, Minarovits J. The LCR of EBV makes Burkitt's lymphoma endemic. Trends Microbiol 2004; 12: 495–499
  • Young LS, Dawson CW, Clark D, et al. Epstein–Barr virus gene expression in nasopharyngeal carcinoma. J Gen Virol 1988; 65(Pt 5)1051–1065
  • Niedobitek G, Young LS, Sam CK, Brooks L, Prasad U, Rickinson AB. Expression of Epstein–Barr virus genes and of lymphocyte activation molecules in undifferentiated nasopharyngeal carcinomas. Am J Pathol 1992; 140: 879–887
  • Rowe DT. Epstein–Barr virus immortalization and latency. Front Biosci 1999; 4: D346–D371
  • Rowe M, Rowe DT, Gregory CD, 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 1987; 6: 2743–2751
  • Gregory CD, Rowe M, Rickinson AB. Different Epstein–Barr virus-B cell interactions in phenotypically distinct clones of a Burkitt's lymphoma cell line. J Gen Virol 1990; 71: 1481–1495
  • Pajic A, Polack A, Staege MS, et al. Elevated expression of c-myc in lymphoblastoid cells does not support an Epstein–Barr virus latency III-to-I switch. J Gen Virol 2001; 82: 3051–3055
  • Pokrovskaja K, Ehlin-Henriksson B, Kiss C, et al. CD40 ligation downregulates EBNA-2 and LMP-1 expression in EBV-transformed lymphoblastoid cell lines. Int J Cancer 2002; 99: 705–712
  • Smith PR, Gao Y, Karran L, Jones MD, Snudden D, Griffin BE. Complex nature of the major viral polyadenylated transcripts in Epstein–Barr virus-associated tumors. J Virol 1993; 67: 3217–3225
  • Sadler RH, Raab-Traub N. The Epstein–Barr virus 3.5-kilobase latent membrane protein 1 mRNA initiates from a TATA-less promoter within the first terminal repeat. J Virol 1995; 69: 4577–4581
  • Sadler RH, Raab-Traub N. Structural analyses of the Epstein–Barr virus BamHI A transcripts. J Virol 1995; 69: 1132–1141
  • Chen H, Huang J, Wu FY, Liao G, Hutt-Fletcher L, Hayward SD. Regulation of expression of the Epstein–Barr virus BamHI-A rightward transcripts. J Virol 2005; 79: 1724–1733
  • Arrand JR, Rymo L. Characterization of the major Epstein–Barr virus-specific RNA in Burkitt lymphoma-derived cells. J Virol 1982; 41: 376–389
  • Felton-Edkins ZA, Kondrashov A, Karali D, et al. Epstein–Barr virus induces cellular transcription factors to allow active expression of EBER genes by RNA polymerase III. J Biol Chem 2006; 281: 33871–33880
  • Lerner MR, Andrews NC, Miller G, Steitz JA. Two small RNAs encoded by Epstein–Barr virus and complexed with protein are precipitated by antibodies from patients with systemic lupus erythematosus. Proc Natl Acad Sci USA 1981; 78: 805–809
  • Toczyski DP, Matera AG, Ward DC, Steitz JA. The Epstein–Barr virus (EBV) small RNA EBER1 binds and relocalizes ribosomal protein L22 in EBV-infected human B lymphocytes. Proc Natl Acad Sci USA 1994; 91: 3463–3467
  • Fok V, Friend K, Steitz JA. Epstein–Barr virus noncoding RNAs are confined to the nucleus, whereas their partner, the human La protein, undergoes nucleocytoplasmic shuttling. J Cell Biol 2006; 173: 319–325
  • Clarke PA, Schwemmle M, Schickinger J, Hilse K, Clemens MJ. Binding of Epstein–Barr virus small RNA EBER-1 to the double-stranded RNA-activated protein kinase DAI. Nucleic Acids Res 1991; 19: 243–248
  • Elia A, Vyas J, Laing KG, Clemens MJ. Ribosomal protein L22 inhibits regulation of cellular activities by the Epstein–Barr virus small RNA EBER-1. Eur J Biochem 2004; 271: 1895–1905
  • 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 1999; 73: 9827–9831
  • Ruf IK, Rhyne PW, Yang C, Cleveland JL, Sample JT. Epstein–Barr virus small RNAs potentiate tumorigenicity of Burkitt lymphoma cells independently of an effect on apoptosis. J Virol 2000; 74: 10223–10228
  • Ruf IK, Lackey KA, Warudkar S, Sample JT. Protection from interferon-induced apoptosis by Epstein–Barr virus small RNAs is not mediated by inhibition of PKR. J Virol 2005; 79: 14562–14569
  • Clemens MJ. Epstein–Barr virus: Inhibition of apoptosis as a mechanism of cell transformation. Int J Biochem Cell Biol 2006; 38: 164–169
  • Sugden B, Warren N. A promoter of Epstein–Barr virus that can function during latent infection can be transactivated by EBNA-1, a viral protein required for viral DNA replication during latent infection. J Virol 1989; 63: 2644–2649
  • Jankelevich S, Kolman JL, Bodnar JW, Miller G. A nuclear matrix attachment region organizes the Epstein–Barr viral plasmid in Raji cells into a single DNA domain. EMBO J 1992; 11: 1165–1176
  • Middleton T, Sugden B. Retention of plasmid DNA in mammalian cells is enhanced by binding of the Epstein–Barr virus replication protein EBNA1. J Virol 1994; 68: 4067–4071
  • White RE, Wade-Martins R, James MR. Sequences adjacent to oriP improve the persistence of Epstein–Barr virus-based episomes in B cells. J Virol 2001; 75: 11249–11252
  • Wensing B, Stuhler A, Jenkins P, Hollyoake M, Karstegl CE, Farrell PJ. Variant chromatin structure of the oriP region of Epstein–Barr virus and regulation of EBER1 expression by upstream sequences and oriP. J Virol 2001; 75: 6235–6241
  • Levitskaya J, Sharipo A, Leonchiks A, Ciechanover A, Masucci MG. Inhibition of ubiquitin/proteasome-dependent protein degradation by the Gly-Ala repeat domain of the Epstein–Barr virus nuclear antigen 1. Proc Natl Acad Sci USA 1997; 94: 12616–12621
  • 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 1982; 44: 834–844
  • Hammerschmidt W, Sugden B. Genetic analysis of immortalizing functions of Epstein–Barr virus in human B lymphocytes. Nature 1989; 340: 393–397
  • Ling PD, Rawlins DR, Hayward SD. The Epstein–Barr virus immortalizing protein EBNA-2 is targeted to DNA by a cellular enhancer-binding protein. Proc Natl Acad Sci USA 1993; 90: 9237–9241
  • Cordier M, Calender A, Billaud M, et al. Stable transfection of Epstein–Barr virus (EBV) nuclear antigen 2 in lymphoma cells containing the EBV P3HR1 genome induces expression of B-cell activation molecules CD21 and CD23. J Virol 1990; 64: 1002–1013
  • Wang F, Tsang SF, Kurilla MG, Cohen JI, Kieff E. Epstein–Barr virus nuclear antigen 2 transactivates latent membrane protein LMP1. J Virol 1990; 64: 3407–3416
  • Mannick JB, Cohen JI, Birkenbach M, Marchini A, Kieff E. The Epstein–Barr virus nuclear protein encoded by the leader of the EBNA RNAs is important in B-lymphocyte transformation. J Virol 1991; 65: 6826–6837
  • Harada S, Kieff E. Epstein–Barr virus nuclear protein LP stimulates EBNA-2 acidic domain-mediated transcriptional activation. J Virol 1997; 71: 6611–6618
  • Nitsche F, Bell A, Rickinson A. Epstein–Barr virus leader protein enhances EBNA-2-mediated transactivation of latent membrane protein 1 expression: A role for the W1W2 repeat domain. J Virol 1997; 71: 6619–6628
  • Sinclair AJ, Palmero I, Peters G, Farrell PJ. EBNA-2 and BNA-LP cooperate to cause G0 to G1 transition during immortalization of resting human B lymphocytes by Epstein–Barr virus. EMBO J 1994; 13: 3321–3328
  • Peng CW, Xue Y, Zhao B, Johannsen E, Kieff E, Harada S. Direct interactions between Epstein–Barr virus leader protein LP and the EBNA2 acidic domain underlie coordinate transcriptional regulation. Proc Natl Acad Sci USA 2004; 101: 1033–1038
  • Szekely L, Pokrovskaja K, Jiang WQ, de The H, Ringertz N, Klein G. The Epstein–Barr virus-encoded nuclear antigen EBNA-5 accumulates in PML-containing bodies. J Virol 1996; 70: 2562–2568
  • 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 1993; 67: 2014–2025
  • Tomkinson B, Kieff E. Use of second-site homologous recombination to demonstrate that Epstein–Barr virus nuclear protein 3B is not important for lymphocyte infection or growth transformation in vitro. J Virol 1992; 66: 2893–2903
  • Waltzer L, Perricaudet M, Sergeant A, Manet E. Epstein–Barr virus EBNA3A and EBNA3C proteins both repress RBP-J kappa-EBNA2-activated transcription by inhibiting the binding of RBP-J kappa to DNA. J Virol 1996; 70: 5909–5915
  • Robertson ES, Lin J, Kieff E. The amino-terminal domains of Epstein–Barr virus nuclear proteins 3A, 3B, and 3C interact with RBPJ(kappa). J Virol 1996; 70: 3068–3074
  • Chen A, Zhao B, Kieff E, Aster JC, Wang F. EBNA-3B- and EBNA-3C-regulated cellular genes in Epstein–Barr virus-immortalized lymphoblastoid cell lines. J Virol 2006; 80: 10139–10150
  • Smith P. Epstein–Barr virus complementary strand transcripts (CSTs/BARTs) and cancer. Semin Cancer Biol 2001; 11: 469–476
  • de Jesus O, Smith PR, Spender LC, 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 2003; 84: 1443–1450
  • Laux G, Dugrillon F, Eckert C, Adam B, Zimber-Strobl U, Bornkamm GW. Identification and characterization of an Epstein–Barr virus nuclear antigen 2-responsive cis element in the bidirectional promoter region of latent membrane protein and terminal protein 2 genes. J Virol 1994; 68: 6947–6958
  • Fennewald S, van Santen V, Kieff E. Nucleotide sequence of an mRNA transcribed in latent growth-transforming virus infection indicates that it may encode a membrane protein. J Virol 1984; 51: 411–419
  • Iwatsuki K, Yamamoto T, Tsuji K, et al. A spectrum of clinical manifestations caused by host immune responses against Epstein–Barr virus infections. Acta Med Okayama 2004; 58: 169–180
  • Andersson J. An Overview of Epstein–Barr virus: From discovery to future directions for treatment and prevention. Herpes 2000; 7: 76–82
  • Niedobitek G, Meru N, Delecluse HJ. Epstein–Barr virus infection and human malignancies. Int J Exp Pathol 2001; 82: 149–170
  • Knecht H, Berger C, Rothenberger S, Odermatt BF, Brousset P. The role of Epstein–Barr virus in neoplastic transformation. Oncology 2001; 60: 289–302
  • Gottschalk S, Rooney CM, Heslop HE. Post-transplant lymphoproliferative disorders. Annu Rev Med 2005; 56: 29–44
  • Brink AA, Dukers DF, van den Brule AJ, et al. Presence of Epstein–Barr virus latency type III at the single cell level in post-transplantation lymphoproliferative disorders and AIDS related lymphomas. J Clin Pathol 1997; 50: 911–918
  • Rickinson AB, Finerty S, Epstein MA. Comparative studies on adult donor lymphocytes infected by EB virus in vivo or in vitro: Origin of transformed cells arising in co-cultures with foetal lymphocytes. Int J Cancer 1977; 19: 775–782
  • Piovan E, Bonaldi L, Indraccolo S, et al. Tumor outgrowth in peripheral blood mononuclear cell-injected SCID mice is not associated with early Epstein–Barr virus reactivation. Leukemia 2003; 17: 1643–1649
  • Hong GK, Gulley ML, Feng WH, Delecluse HJ, Holley-Guthrie E, Kenney SC. Epstein–Barr virus lytic infection contributes to lymphoproliferative disease in a SCID mouse model. J Virol 2005; 79: 13993–14003
  • Burns DM, Crawford DH. Epstein–Barr virus-specific cytotoxic T-lymphocytes for adoptive immunotherapy of post-transplant lymphoproliferative disease. Blood Rev 2004; 18: 193–209
  • Gregory CD, Murray RJ, Edwards CF, Rickinson AB. Downregulation of cell adhesion molecules LFA-3 and ICAM-1 in Epstein–Barr virus-positive Burkitt's lymphoma underlies tumor cell escape from virus-specific T cell surveillance. J Exp Med 1988; 167: 1811–1824
  • van den Bosch CA. Is endemic Burkitt's lymphoma an alliance between three infections and a tumour promoter?. Lancet Oncol 2004; 5: 738–746
  • Magrath I. The pathogenesis of Burkitt's lymphoma. Adv Cancer Res 1990; 55: 133–270
  • Hecht JL, Aster JC. Molecular biology of Burkitt's lymphoma. J Clin Oncol 2000; 18: 3707–3721
  • Cheng SW, Davies KP, Yung E, Beltran RJ, Yu J, Kalpana GV. c-MYC interacts with INI1/hSNF5 and requires the SWI/SNF complex for transactivation function. Nat Genet 1999; 22: 102–105
  • Waitz W, Loidl P. Cell cycle dependent association of c-myc protein with the nuclear matrix. Oncogene 1991; 6: 29–35
  • Goossens T, Klein U, Kuppers R. Frequent occurrence of deletions and duplications during somatic hypermutation: Implications for oncogene translocations and heavy chain disease. Proc Natl Acad Sci USA 1998; 95: 2463–2468
  • Rooney CM, Rowe M, Wallace LE, Rickinson AB. Epstein–Barr virus-positive Burkitt's lymphoma cells not recognized by virus-specific T-cell surveillance. Nature 1985; 317: 629–631
  • Lenoir GM, Bornkamm G. Burkitt's lymphoma, a human cancer model for the study of the multistep dvelopment of cancer: Proposal for a new scenario. Advances in viral oncology, G Klein. Raven Press, New York 1987; 173–206
  • Klein G. In defense of the “old” Burkitt lymphoma scenario. Advances in viral oncology, G Klein. Raven Press, New York 1987; 207–211
  • Rossi G, Bonetti F. EBV and Burkitt's lymphoma. N Engl J Med 2004; 350: 2621
  • Magrath I, Jain V, Bhatia K. Epstein–Barr virus and Burkitt's lymphoma. Semin Cancer Biol 1992; 3: 285–295
  • Kelly G, Bell A, Rickinson A. Epstein–Barr virus-associated Burkitt lymphomagenesis selects for downregulation of the nuclear antigen EBNA2. Nat Med 2002; 8: 1098–1104
  • Niller HH, Salamon D, Ilg K, et al. The in vivo binding site for oncoprotein c-Myc in the promoter for Epstein–Barr virus (EBV) encoding RNA (EBER) 1 suggests a specific role for EBV in lymphomagenesis. Med Sci Monit 2003; 9: HY1–HY9
  • Niller HH, Salamon D, Ilg K, et al. EBV-associated neoplasms: Alternative pathogenetic pathways. Med Hypotheses 2004; 62: 387–391
  • Pelengaris S, Khan M, Evan GI. Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 2002; 109: 321–334
  • Marshall NA, Christie LE, Munro LR, et al. Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 2004; 103: 1755–1762
  • Kuppers R, Schwering I, Brauninger A, Rajewsky K, Hansmann ML. Biology of Hodgkin's lymphoma. Ann Oncol 2002; 13(Suppl 1)11–18
  • Hjalgrim H, Askling J, Rostgaard K, et al. Characteristics of Hodgkin's lymphoma after infectious mononucleosis. N Engl J Med 2003; 349: 1324–1332
  • Weiss LM, Movahed LA, Warnke RA, Sklar J. Detection of Epstein–Barr viral genomes in Reed–Sternberg cells of Hodgkin's disease. N Engl J Med 1989; 320: 502–506
  • Bargou RC, Emmerich F, Krappmann D, et al. Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells. J Clin Invest 1997; 100: 2961–2969
  • Duraiswamy J, Sherritt M, Thomson S, et al. Therapeutic LMP1 polyepitope vaccine for EBV-associated Hodgkin disease and nasopharyngeal carcinoma. Blood 2003; 101: 3150–3156
  • Bollard CM, Aguilar L, Straathof KC, et al. Cytotoxic T lymphocyte therapy for Epstein–Barr virus+ Hodgkin's disease. J Exp Med 2004; 200: 1623–1633
  • Lo KW, To KF, Huang DP. Focus on nasopharyngeal carcinoma. Cancer Cell 2004; 5: 423–428
  • Wolf H, zur Hausen H, Becker V. EB viral genomes in epithelial nasopharyngeal carcinoma cells. Nat New Biol 1973; 244: 245–247
  • Desgranges C, Wolf H, de The G, et al. Nasopharyngeal carcinoma X. Presence of Epstein–Barr genomes in separated epithelial cells of tumours in patients from Singapore, Tunisia and Kenya. Int J Cancer 1975; 16: 7–15
  • Nicholls JM, Agathanggelou A, Fung K, Zeng X, Niedobitek G. The association of squamous cell carcinomas of the nasopharynx with Epstein–Barr virus shows geographical variation reminiscent of Burkitt's lymphoma. J Pathol 1997; 183: 164–168
  • Hildesheim A, Apple RJ, Chen CJ, et al. Association of HLA class I and II alleles and extended haplotypes with nasopharyngeal carcinoma in Taiwan. J Natl Cancer Inst 2002; 94: 1780–1789
  • Zeng Y. Seroepidemiological studies on nasopharyngeal carcinoma in China. Adv Cancer Res 1985; 44: 121–138
  • Ito Y, Ohigashi H, Koshimizu K, Yi Z. Epstein–Barr virus-activating principle in the ether extracts of soils collected from under plants which contain active diterpene esters. Cancer Lett 1983; 19: 113–117
  • Ho JH, Huang DP, Fong YY. Salted fish and nasopharyngeal carcinoma in southern Chinese. Lancet 1978; 2: 626
  • Henle G, Henle W. Epstein–Barr virus-specific IgA serum antibodies as an outstanding feature of nasopharyngeal carcinoma. Int J Cancer 1976; 17: 1–7
  • Straathof KC, Bollard CM, Popat U, et al. Treatment of nasopharyngeal carcinoma with Epstein–Barr virus-specific T lymphocytes. Blood 2005; 105: 1898–1904
  • Osato T, Imai S. Epstein–Barr virus and gastric carcinoma. Semin Cancer Biol 1996; 7: 175–182
  • zur Hausen A, Brink AA, Craanen ME, Middeldorp JM, Meijer CJ, van den Brule AJ. Unique transcription pattern of Epstein–Barr virus (EBV) in EBV-carrying gastric adenocarcinomas: Expression of the transforming BARF1 gene. Cancer Res 2000; 60: 2745–2748
  • Seto E, Yang L, Middeldorp J, 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 2005; 76: 82–88
  • McClain KL, Leach CT, Jenson HB, et al. Association of Epstein–Barr virus with leiomyosarcomas in children with AIDS. N Engl J Med 1995; 332: 12–18
  • Lee ES, Locker J, Nalesnik M, et al. The association of Epstein–Barr virus with smooth-muscle tumors occurring after organ transplantation. N Engl J Med 1995; 332: 19–25
  • Jones JF, Shurin S, Abramowsky C, et al. T-cell lymphomas containing Epstein–Barr viral DNA in patients with chronic Epstein–Barr virus infections. N Engl J Med 1988; 318: 733–741
  • Pallesen G, Hamilton-Dutoit SJ, Zhou X. The association of Epstein–Barr virus (EBV) with T cell lymphoproliferations and Hodgkin's disease: Two new developments in the EBV field. Adv Cancer Res 1993; 62: 179–239
  • Harabuchi Y, Yamanaka N, Kataura A, et al. Epstein–Barr virus in nasal T-cell lymphomas in patients with lethal midline granuloma. Lancet 1990; 335: 128–130
  • Minarovits J, Hu LF, Imai S, et al. Clonality, expression and methylation patterns of the Epstein–Barr virus genomes in lethal midline granulomas classified as peripheral angiocentric T cell lymphomas. J Gen Virol 1994; 75: 77–84
  • Labrecque LG, Barnes DM, Fentiman IS, Griffin BE. Epstein–Barr virus in epithelial cell tumors: A breast cancer study. Cancer Res 1995; 55: 39–45
  • Bonnet M, Guinebretiere JM, Kremmer E, et al. Detection of Epstein–Barr virus in invasive breast cancers. J Natl Cancer Inst 1999; 91: 1376–1381
  • Fina F, Romain S, Ouafik L, et al. Frequency and genome load of Epstein–Barr virus in 509 breast cancers from different geographical areas. Br J Cancer 2001; 84: 783–790
  • Arbach H, Viglasky V, Lefeu F, et al. Epstein–Barr virus (EBV) genome and expression in breast cancer tissue: Effect of EBV infection of breast cancer cells on resistance to paclitaxel (Taxol). J Virol 2006; 80: 845–853
  • Chu PG, Chang KL, Chen YY, Chen WG, Weiss LM. No significant association of Epstein–Barr virus infection with invasive breast carcinoma. Am J Pathol 2001; 159: 571–578
  • Herrmann K, Niedobitek G. Lack of evidence for an association of Epstein–Barr virus infection with breast carcinoma. Breast Cancer Res 2002; 5: R13–R17
  • Deshpande CG, Badve S, Kidwai N, Longnecker R. Lack of expression of the Epstein–Barr Virus (EBV) gene products, EBERs, EBNA1, LMP1, and LMP2A, in breast cancer cells. Lab Invest 2002; 82: 1193–1199
  • Murray PG, Lissauer D, Junying J, et al. Reactivity with A monoclonal antibody to Epstein–Barr virus (EBV) nuclear antigen 1 defines a subset of aggressive breast cancers in the absence of the EBV genome. Cancer Res 2003; 63: 2338–2343
  • Hamilton-Dutoit SJ, Raphael M, Audouin J, et al. In situ demonstration of Epstein–Barr virus small RNAs (EBER 1) in acquired immunodeficiency syndrome-related lymphomas: Correlation with tumor morphology and primary site. Blood 1993; 82: 619–624
  • Timms JM, Bell A, Flavell JR, et al. Target cells of Epstein–Barr-virus (EBV)-positive post-transplant lymphoproliferative disease: Similarities to EBV-positive Hodgkin's lymphoma. Lancet 2003; 361: 217–223
  • Yin CC, Medeiros LJ, Abruzzo LV, Jones D, Farhood AI, Thomazy VA. EBV-associated B- and T-cell posttransplant lymphoproliferative disorders following primary EBV infection in a kidney transplant recipient. Am J Clin Pathol 2005; 123: 222–228
  • Meerbach A, Gruhn B, Egerer R, Reischl U, Zintl F, Wutzler P. Semiquantitative PCR analysis of Epstein–Barr virus DNA in clinical samples of patients with EBV-associated diseases. J Med Virol 2001; 65: 348–357
  • Wagner HJ, Wessel M, Jabs W, et al. Patients at risk for development of posttransplant lymphoproliferative disorder: Plasma versus peripheral blood mononuclear cells as material for quantification of Epstein–Barr viral load by using real-time quantitative polymerase chain reaction. Transplantation 2001; 72: 1012–1019
  • Swinnen LJ. Transplantation-related lymphoproliferative disorder: A model for human immunodeficiency virus-related lymphomas. Semin Oncol 2000; 27: 402–408
  • Williams H, Crawford DH. Epstein–Barr virus: The impact of scientific advances on clinical practice. Blood 2006; 107: 862–869
  • Milone MC, Tsai DE, Hodinka RL, et al. Treatment of primary Epstein–Barr virus infection in patients with X-linked lymphoproliferative disease using B-cell-directed therapy. Blood 2005; 105: 994–996
  • Van Baarle D, Wolthers KC, Hovenkamp E, et al. Absolute level of Epstein–Barr virus DNA in human immunodeficiency virus type 1 infection is not predictive of AIDS-related non-Hodgkin lymphoma. J Infect Dis 2002; 186: 405–409
  • Fellner MD, Durand K, Correa RM, et al. Circulating Epstein–Barr virus (EBV) in HIV-infected patients and its relation with primary brain lymphoma. Int J Infect Dis 2007; 11: 172–178
  • Piriou ER, van Dort K, Nanlohy NM, Miedema F, Van Oers MH, Van Baarle D. Altered EBV viral load setpoint after HIV seroconversion is in accordance with lack of predictive value of EBV load for the occurrence of AIDS-related non-Hodgkin lymphoma. J Immunol 2004; 172: 6931–6937
  • Ling PD, Vilchez RA, Keitel WA, et al. Epstein–Barr virus DNA loads in adult human immunodeficiency virus type 1-infected patients receiving highly active antiretroviral therapy. Clin Infect Dis 2003; 37: 1244–1249
  • Righetti E, Ballon G, Ometto L, et al. Dynamics of Epstein–Barr virus in HIV-1-infected subjects on highly active antiretroviral therapy. AIDS 2002; 16: 63–73
  • Stevens SJ, Blank BS, Smits PH, Meenhorst PL, Middeldorp JM. High Epstein–Barr virus (EBV) DNA loads in HIV-infected patients: Correlation with antiretroviral therapy and quantitative EBV serology. AIDS 2002; 16: 993–1001
  • Van Baarle D, Hovenkamp E, Callan MF, et al. Dysfunctional Epstein–Barr virus (EBV)-specific CD8(+) T lymphocytes and increased EBV load in HIV-1 infected individuals progressing to AIDS-related non-Hodgkin lymphoma. Blood 2001; 98: 146–155
  • Bossolasco S, Falk KI, Ponzoni M, et al. Ganciclovir is associated with low or undetectable Epstein–Barr virus DNA load in cerebrospinal fluid of patients with HIV-related primary central nervous system lymphoma. Clin Infect Dis 2006; 42: e21–e25
  • Fan W, Bubman D, Chadburn A, Harrington WJ, Jr., Cesarman E, Knowles DM. Distinct subsets of primary effusion lymphoma can be identified based on their cellular gene expression profile and viral association. J Virol 2005; 79: 1244–1251
  • Facer CA, Playfair JH. Malaria, Epstein–Barr virus, and the genesis of lymphomas. Adv Cancer Res 1989; 53: 33–72
  • Lam KM, Syed N, Whittle H, Crawford DH. Circulating Epstein–Barr virus-carrying B cells in acute malaria. Lancet 1991; 337: 876–878
  • Yone CL, Kube D, Kremsner PG, Luty AJ. Persistent Epstein–Barr viral reactivation in young African children with a history of severe Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 2006; 100: 669–676
  • Rasti N, Falk KI, Donati D, et al. Circulating Epstein–Barr virus in children living in malaria-endemic areas. Scand J Immunol 2005; 61: 461–465
  • Moormann AM, Chelimo K, Sumba OP, et al. Exposure to holoendemic malaria results in elevated Epstein–Barr virus loads in children. J Infect Dis 2005; 191: 1233–1238
  • Donati D, Espmark E, Kironde F, et al. Clearance of circulating Epstein–Barr virus DNA in children with acute malaria after antimalaria treatment. J Infect Dis 2006; 193: 971–977
  • Donati D, Zhang LP, Chene A, et al. Identification of a polyclonal B-cell activator in Plasmodium falciparum. Infect Immun 2004; 72: 5412–5418
  • Donati D, Mok B, Chene A, et al. Increased B cell survival and preferential activation of the memory compartment by a malaria polyclonal B cell activator. J Immunol 2006; 177: 3035–3044
  • Chene A, Donati D, Guerreiro-Cacais AO, et al. Molecular link between malaria and Epstein–Barr virus reactivation. PLoS Pathog 2007; 3: e80
  • Evans AS, Rothfield NF, Niederman JC. Raised antibody titres to E.B. virus in systemic lupus erythematosus. Lancet 1971; 1: 167–168
  • Pender MP. Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol 2003; 24: 584–588
  • Wong M, Tsao BP. Current topics in human SLE genetics. Springer Semin Immunopathol 2006; 28: 97–107
  • Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: The role of infection. Ann Neurol 2007; 61: 288–299
  • Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann Neurol 2007; 61: 504–513
  • Poser CM. Notes on the pathogenesis of multiple sclerosis. Clin Neurosci 1994; 2: 258–265
  • Reiber H, Ungefehr S, Jacobi C. The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult Scler 1998; 4: 111–117
  • Grufferman S, Delzell E. Epidemiology of Hodgkin's disease. Epidemiol Rev 1984; 6: 76–106
  • Newell GR. Etiology of multiple sclerosis and Hodgkin's disease. Am J Epidemiol 1970; 91: 119–122
  • Olerup O, Hillert J. HLA class II-associated genetic susceptibility in multiple sclerosis: A critical evaluation. Tissue Antigens 1991; 38: 1–15
  • Kurtzke JF. Epidemiologic evidence for multiple sclerosis as an infection. Clin Microbiol Rev 1993; 6: 382–427
  • Kurtzke JF, Heltberg A. Multiple sclerosis in the Faroe Islands: An epitome. J Clin Epidemiol 2001; 54: 1–22
  • Perron H, Garson JA, Bedin F, et al. Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. The Collaborative Research Group on Multiple Sclerosis. Proc Natl Acad Sci USA 1997; 94: 7583–7588
  • Batinac T, Petranovic D, Zamolo G, Petranovic D, Ruzic A. Lyme borreliosis and multiple sclerosis are associated with primary effusion lymphoma. Med Hypotheses 2007; 69: 117–119
  • Gilden DH. Infectious causes of multiple sclerosis. Lancet Neurol 2005; 4: 195–202
  • Christensen T. Association of human endogenous retroviruses with multiple sclerosis and possible interactions with herpes viruses. Rev Med Virol 2005; 15: 179–211
  • Giovannoni G, Cutter GR, Lunemann J, et al. Infectious causes of multiple sclerosis. Lancet Neurol 2006; 5: 887–894
  • Alotaibi S, Kennedy J, Tellier R, Stephens D, Banwell B. Epstein–Barr virus in pediatric multiple sclerosis. JAMA 2004; 291: 1875–1879
  • Pohl D, Krone B, Rostasy K, et al. High seroprevalence of Epstein–Barr virus in children with multiple sclerosis. Neurology 2006; 67: 2063–2065
  • Haahr S, Hollsberg P. Multiple sclerosis is linked to Epstein–Barr virus infection. Rev Med Virol 2006; 16: 297–310
  • Nielsen TR, Rostgaard K, Nielsen NM, et al. Multiple sclerosis after infectious mononucleosis. Arch Neurol 2007; 64: 72–75
  • DeLorenze GN, Munger KL, Lennette ET, Orentreich N, Vogelman JH, Ascherio A. Epstein–Barr virus and multiple sclerosis: Evidence of association from a prospective study with long-term follow-up. Arch Neurol 2006; 63: 839–844
  • Nielsen TR, Pedersen M, Rostgaard K, Frisch M, Hjalgrim H. Correlations between Epstein–Barr virus antibody levels and risk factors for multiple sclerosis in healthy individuals. Mult Scler 2007; 13: 420–423
  • Sundstrom P, Juto P, Wadell G, et al. An altered immune response to Epstein–Barr virus in multiple sclerosis: A prospective study. Neurology 2004; 62: 2277–2282
  • Bray PF, Luka J, Bray PF, Culp KW, Schlight JP. Antibodies against Epstein–Barr nuclear antigen (EBNA) in multiple sclerosis CSF, and two pentapeptide sequence identities between EBNA and myelin basic protein. Neurology 1992; 42: 1798–1804
  • Cepok S, Zhou D, Srivastava R, et al. Identification of Epstein–Barr virus proteins as putative targets of the immune response in multiple sclerosis. J Clin Invest 2005; 115: 1352–1360
  • Wucherpfennig KW, Strominger JL. Molecular mimicry in T cell-mediated autoimmunity: Viral peptides activate human T cell clones specific for myelin basic protein. Cell 1995; 80: 695–705
  • Lang HL, Jacobsen H, Ikemizu S, et al. A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat Immunol 2002; 3: 940–943
  • Holmoy T, Vartdal F. Cerebrospinal fluid T cells from multiple sclerosis patients recognize autologous Epstein–Barr virus-transformed B cells. J Neurovirol 2004; 10: 52–56
  • Holmoy T, Kvale EO, Vartdal F. Cerebrospinal fluid CD4+ T cells from a multiple sclerosis patient cross-recognize Epstein–Barr virus and myelin basic protein. J Neurovirol 2004; 10: 278–283
  • Lunemann JD, Edwards N, Muraro PA, et al. Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. Brain 2006; 129: 1493–1506
  • Gronen F, Ruprecht K, Weissbrich B, et al. Frequency analysis of HLA-B7-restricted Epstein–Barr virus-specific cytotoxic T lymphocytes in patients with multiple sclerosis and healthy controls. J Neuroimmunol 2006; 180: 185–192
  • Swanson-Mungerson M, Longnecker R. Epstein–Barr virus latent membrane protein 2A and autoimmunity. Trends Immunol 2007; 28: 213–218
  • Antony JM, van Marle G, Opii W, et al. Human endogenous retrovirus glycoprotein-mediated induction of redox reactants causes oligodendrocyte death and demyelination. Nat Neurosci 2004; 7: 1088–1095
  • Cooper GS, Dooley MA, Treadwell EL, St Clair EW, Parks CG, Gilkeson GS. Hormonal, environmental, and infectious risk factors for developing systemic lupus erythematosus. Arthritis Rheum 1998; 41: 1714–1724
  • Hinterberger M, Pettersson I, Steitz JA. Isolation of small nuclear ribonucleoproteins containing U1, U2, U4, U5, and U6 RNAs. J Biol Chem 1983; 258: 2604–2613
  • Maddison PJ, Reichlin M. Quantitation of precipitating antibodies to certain soluble nuclear antigens in SLE. Arthritis Rheum 1977; 20: 819–824
  • Bhat NM, Bieber MM, Yang YC, Leu YS, van Vollenhoven RF, Teng NN. B cell lymphoproliferative disorders and VH4-34 gene encoded antibodies. Hum Antibodies 2004; 13: 63–68
  • van Vollenhoven RF, Bieber MM, Powell MJ, et al. VH4-34 encoded antibodies in systemic lupus erythematosus: A specific diagnostic marker that correlates with clinical disease characteristics. J Rheumatol 1999; 26: 1727–1733
  • Heinlen LD, McClain MT, Merrill J, et al. Clinical criteria for systemic lupus erythematosus precede diagnosis, and associated autoantibodies are present before clinical symptoms. Arthritis Rheum 2007; 56: 2344–2351
  • Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003; 349: 1526–1533
  • James JA, Harley JB. B-cell epitope spreading in autoimmunity. Immunol Rev 1998; 164: 185–200
  • Tsokos GC, Magrath IT, Balow JE. Epstein–Barr virus induces normal B cell responses but defective suppressor T cell responses in patients with systemic lupus erythematosus. J Immunol 1983; 131: 1797–1801
  • Harley JB, Harley IT, Guthridge JM, James JA. The curiously suspicious: A role for Epstein–Barr virus in lupus. Lupus 2006; 15: 768–777
  • Croker JA, Kimberly RP. Genetics of susceptibility and severity in systemic lupus erythematosus. Curr Opin Rheumatol 2005; 17: 529–537
  • Ronnblom L, Eloranta ML, Alm GV. The type I interferon system in systemic lupus erythematosus. Arthritis Rheum 2006; 54: 408–420
  • Savarese E, Chae OW, Trowitzsch S, et al. U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7. Blood 2006; 107: 3229–3234
  • Berghofer B, Frommer T, Haley G, Fink L, Bein G, Hackstein H. TLR7 ligands induce higher IFN-alpha production in females. J Immunol 2006; 177: 2088–2096
  • Parks CG, Cooper GS, Hudson LL, et al. Association of Epstein–Barr virus with systemic lupus erythematosus: Effect modification by race, age, and cytotoxic T lymphocyte-associated antigen 4 genotype. Arthritis Rheum 2005; 52: 1148–1159
  • Sarzi-Puttini P, Atzeni F, Iaccarino L, Doria A. Environment and systemic lupus erythematosus: An overview. Autoimmunity 2005; 38: 465–472
  • Zandman-Goddard G, Shoenfeld Y. Infections and SLE. Autoimmunity 2005; 38: 473–485
  • Kowal C, Weinstein A, Diamond B. Molecular mimicry between bacterial and self antigen in a patient with systemic lupus erythematosus. Eur J Immunol 1999; 29: 1901–1911
  • Hemmerich P, Neu E, Macht M, Peter HH, Krawinkel U, von Mikecz A. Correlation between chlamydial infection and autoimmune response: Molecular mimicry between RNA polymerase major sigma subunit from Chlamydia trachomatis and human L7. Eur J Immunol 1998; 28: 3857–3866
  • Pyun EH, Pisetsky DS, Gilkeson GS. The fine specificity of monoclonal anti-DNA antibodies induced in normal mice by immunization with bacterial DNA. J Autoimmun 1993; 6: 11–26
  • Gilkeson GS, Pippen AM, Pisetsky DS. Induction of cross-reactive anti-dsDNA antibodies in preautoimmune NZB/NZW mice by immunization with bacterial DNA. J Clin Invest 1995; 95: 1398–1402
  • Shoenfeld Y, Vilner Y, Coates AR, et al. Monoclonal anti-tuberculosis antibodies react with DNA, and monoclonal anti-DNA autoantibodies react with Mycobacterium tuberculosis. Clin Exp Immunol 1986; 66: 255–261
  • Hardgrave KL, Neas BR, Scofield RH, Harley JB. Antibodies to vesicular stomatitis virus proteins in patients with systemic lupus erythematosus and in normal subjects. Arthritis Rheum 1993; 36: 962–970
  • Rekvig OP, Moens U, Sundsfjord A, et al. Experimental expression in mice and spontaneous expression in human SLE of polyomavirus T-antigen. A molecular basis for induction of antibodies to DNA and eukaryotic transcription factors. J Clin Invest 1997; 99: 2045–2054
  • Perl A, Colombo E, Dai H, et al. Antibody reactivity to the HRES-1 endogenous retroviral element identifies a subset of patients with systemic lupus erythematosus and overlap syndromes. Correlation with antinuclear antibodies and HLA class II alleles. Arthritis Rheum 1995; 38: 1660–1671
  • Rider JR, Ollier WE, Lock RJ, Brookes ST, Pamphilon DH. Human cytomegalovirus infection and systemic lupus erythematosus. Clin Exp Rheumatol 1997; 15: 405–409
  • Ishikawa O, Abe M, Miyachi Y. Herpes zoster in Japanese patients with systemic lupus erythematosus. Clin Exp Dermatol 1999; 24: 327–328
  • James JA, Harley JB, Scofield RH. Epstein–Barr virus and systemic lupus erythematosus. Curr Opin Rheumatol 2006; 18: 462–467
  • James JA, Neas BR, Moser KL, et al. Systemic lupus erythematosus in adults is associated with previous Epstein–Barr virus exposure. Arthritis Rheum 2001; 44: 1122–1126
  • James JA, Kaufman KM, Farris AD, Taylor-Albert E, Lehman TJ, Harley JB. An increased prevalence of Epstein–Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus. J Clin Invest 1997; 100: 3019–3026
  • McClain MT, Heinlen LD, Dennis GJ, Roebuck J, Harley JB, James JA. Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. Nat Med 2005; 11: 85–89
  • James JA, Gross T, Scofield RH, Harley JB. Immunoglobulin epitope spreading and autoimmune disease after peptide immunization: Sm B/B′-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity. J Exp Med 1995; 181: 453–461
  • Arbuckle MR, Reichlin M, Harley JB, James JA. Shared early autoantibody recognition events in the development of anti-Sm B/B′ in human lupus. Scand J Immunol 1999; 50: 447–455
  • James JA, Harley JB. A model of peptide-induced lupus autoimmune B cell epitope spreading is strain specific and is not H-2 restricted in mice. J Immunol 1998; 160: 502–508
  • Arbuckle MR, Gross T, Scofield RH, et al. Lupus humoral autoimmunity induced in a primate model by short peptide immunization. J Investig Med 1998; 46: 58–65
  • James JA, Harley JB. Linear epitope mapping of an Sm B/B′ polypeptide. J Immunol 1992; 148: 2074–2079
  • McClain MT, Poole BD, Bruner BF, Kaufman KM, Harley JB, James JA. An altered immune response to Epstein–Barr nuclear antigen 1 in pediatric systemic lupus erythematosus. Arthritis Rheum 2006; 54: 360–368
  • James JA, Scofield RH, Harley JB. Lupus humoral autoimmunity after short peptide immunization. Ann NY Acad Sci 1997; 815: 124–127
  • Sundar K, Jacques S, Gottlieb P, et al. Expression of the Epstein–Barr virus nuclear antigen-1 (EBNA-1) in the mouse can elicit the production of anti-dsDNA and anti-Sm antibodies. J Autoimmun 2004; 23: 127–140
  • Kaufman KM, Kirby MY, Harley JB, James JA. Peptide mimics of a major lupus epitope of SmB/B′. Ann NY Acad Sci 2003; 987: 215–229
  • Incaprera M, Rindi L, Bazzichi A, Garzelli C. Potential role of the Epstein–Barr virus in systemic lupus erythematosus autoimmunity. Clin Exp Rheumatol 1998; 16: 289–294
  • Sabbatini A, Bombardieri S, Migliorini P. Autoantibodies from patients with systemic lupus erythematosus bind a shared sequence of SmD and Epstein–Barr virus-encoded nuclear antigen EBNA I. Eur J Immunol 1993; 23: 1146–1152
  • Yamazaki M, Kitamura R, Kusano S, et al. Elevated immunoglobulin G antibodies to the proline-rich amino-terminal region of Epstein–Barr virus nuclear antigen-2 in sera from patients with systemic connective tissue diseases and from a subgroup of Sjogren's syndrome patients with pulmonary involvements. Clin Exp Immunol 2005; 139: 558–568
  • Yu SF, Wu HC, Tsai WC, et al. Detecting Epstein–Barr virus DNA from peripheral blood mononuclear cells in adult patients with systemic lupus erythematosus in Taiwan. Med Microbiol Immunol 2005; 194: 115–120
  • Moon UY, Park SJ, Oh ST, et al. Patients with systemic lupus erythematosus have abnormally elevated Epstein–Barr virus load in blood. Arthritis Res Ther 2004; 6: R295–R302
  • Kang I, Quan T, Nolasco H, et al. Defective control of latent Epstein–Barr virus infection in systemic lupus erythematosus. J Immunol 2004; 172: 1287–1294
  • Gross AJ, Hochberg D, Rand WM, Thorley-Lawson DA. EBV and systemic lupus erythematosus: A new perspective. J Immunol 2005; 174: 6599–6607
  • Berner BR, Tary-Lehmann M, Yonkers NL, Askari AD, Lehmann PV, Anthony DD. Phenotypic and functional analysis of EBV-specific memory CD8 cells in SLE. Cell Immunol 2005; 235: 29–38
  • He B, Raab-Traub N, Casali P, Cerutti A. EBV-encoded latent membrane protein 1 cooperates with BAFF/BLyS and APRIL to induce T cell-independent Ig heavy chain class switching. J Immunol 2003; 171: 5215–5224
  • Mackay F, Ambrose C. The TNF family members BAFF and APRIL: The growing complexity. Cytokine Growth Factor Rev 2003; 14: 311–324
  • Mackay F, Woodcock SA, Lawton P, et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med 1999; 190: 1697–1710
  • Khare SD, Sarosi I, Xia XZ, et al. Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc Natl Acad Sci USA 2000; 97: 3370–3375
  • Groom J, Kalled SL, Cutler AH, et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren's syndrome. J Clin Invest 2002; 109: 59–68
  • Fletcher CA, Sutherland AP, Groom JR, et al. Development of nephritis but not sialadenitis in autoimmune-prone BAFF transgenic mice lacking marginal zone B cells. Eur J Immunol 2006; 36: 2504–2514
  • Yurasov S, Wardemann H, Hammersen J, et al. Defective B cell tolerance checkpoints in systemic lupus erythematosus. J Exp Med 2005; 201: 703–711
  • Thien M, Phan TG, Gardam S, et al. Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches. Immunity 2004; 20: 785–798
  • Wakabayashi C, Adachi T, Wienands J, Tsubata T. A distinct signaling pathway used by the IgG-containing B cell antigen receptor. Science 2002; 298: 2392–2395
  • McClain MT, Rapp EC, Harley JB, James JA. Infectious mononucleosis patients temporarily recognize a unique, cross-reactive epitope of Epstein–Barr virus nuclear antigen-1. J Med Virol 2003; 70: 253–257
  • Costenbader KH, Karlson EW. Epstein–Barr virus and rheumatoid arthritis: Is there a link?. Arthritis Res Ther 2006; 8: 204
  • Sawada S, Takei M, Inomata H, Nozaki T, Shiraiwa H. What is after cytokine-blocking therapy, a novel therapeutic target-synovial Epstein–Barr virus for rheumatoid arthritis. Autoimmun Rev 2007; 6: 126–130
  • Oliver JE, Silman AJ. Risk factors for the development of rheumatoid arthritis. Scand J Rheumatol 2006; 35: 169–174
  • Stastny P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med 1978; 298: 869–871
  • Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987; 30: 1205–1213
  • Jilg W, Bogedain C, Mairhofer H, Gu SY, Wolf H. The Epstein–Barr virus-encoded glycoprotein gp 110 (BALF 4) can serve as a target for antibody-dependent cell-mediated cytotoxicity (ADCC). Virology 1994; 202: 974–977
  • Saal JG, Krimmel M, Steidle M, et al. Synovial Epstein–Barr virus infection increases the risk of rheumatoid arthritis in individuals with the shared HLA-DR4 epitope. Arthritis Rheum 1999; 42: 1485–1496
  • Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog L. A gene–environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum 2004; 50: 3085–3092
  • Klareskog L, Stolt P, Lundberg K, et al. A new model for an etiology of rheumatoid arthritis: Smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 2006; 54: 38–46
  • Massa M, Mazzoli F, Pignatti P, et al. Proinflammatory responses to self HLA epitopes are triggered by molecular mimicry to Epstein–Barr virus proteins in oligoarticular juvenile idiopathic arthritis. Arthritis Rheum 2002; 46: 2721–2729
  • Franssila R, Hedman K. Infection and musculoskeletal conditions: Viral causes of arthritis. Best Pract Res Clin Rheumatol 2006; 20: 1139–1157
  • Symmons DP, Bankhead CR, Harrison BJ, et al. Blood transfusion, smoking, and obesity as risk factors for the development of rheumatoid arthritis: Results from a primary care-based incident case-control study in Norfolk, England. Arthritis Rheum 1997; 40: 1955–1961
  • Bond C, Cleland LG. Rheumatoid arthritis: Are pets implicated in its etiology?. Semin Arthritis Rheum 1996; 25: 308–317
  • Ray CG, Gall EP, Minnich LL, Roediger J, De Benedetti C, Corrigan JJ. Acute polyarthritis associated with active Epstein–Barr virus infection. JAMA 1982; 248: 2990–2993
  • Alspaugh MA, Jensen FC, Rabin H, Tan EM. Lymphocytes transformed by Epstein–Barr virus. Induction of nuclear antigen reactive with antibody in rheumatoid arthritis. J Exp Med 1978; 147: 1018–1027
  • Catalano MA, Carson DA, Slovin SF, Richman DD, Vaughan JH. Antibodies to Epstein–Barr virus-determined antigens in normal subjects and in patients with seropositive rheumatoid arthritis. Proc Natl Acad Sci USA 1979; 76: 5825–5828
  • Blaschke S, Schwarz G, Moneke D, Binder L, Muller G, Reuss-Borst M. Epstein–Barr virus infection in peripheral blood mononuclear cells, synovial fluid cells, and synovial membranes of patients with rheumatoid arthritis. J Rheumatol 2000; 27: 866–873
  • Tosato G, Steinberg AD, Yarchoan R, et al. Abnormally elevated frequency of Epstein–Barr virus-infected B cells in the blood of patients with rheumatoid arthritis. J Clin Invest 1984; 73: 1789–1795
  • Ferrell PB, Aitcheson CT, Pearson GR, Tan EM. Seroepidemiological study of relationships between Epstein–Barr virus and rheumatoid arthritis. J Clin Invest 1981; 67: 681–687
  • Balandraud N, Meynard JB, Auger I, et al. Epstein–Barr virus load in the peripheral blood of patients with rheumatoid arthritis: Accurate quantification using real-time polymerase chain reaction. Arthritis Rheum 2003; 48: 1223–1228
  • Takeda T, Mizugaki Y, Matsubara L, Imai S, Koike T, Takada K. Lytic Epstein–Barr virus infection in the synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum 2000; 43: 1218–1225
  • Takei M, Mitamura K, Fujiwara S, et al. Detection of Epstein–Barr virus-encoded small RNA 1 and latent membrane protein 1 in synovial lining cells from rheumatoid arthritis patients. Int Immunol 1997; 9: 739–743
  • Fox R, Sportsman R, Rhodes G, Luka J, Pearson G, Vaughan J. Rheumatoid arthritis synovial membrane contains a 62,000-molecular-weight protein that shares an antigenic epitope with the Epstein–Barr virus-encoded associated nuclear antigen. J Clin Invest 1986; 77: 1539–1547
  • Birkenfeld P, Haratz N, Klein G, Sulitzeanu D. Cross-reactivity between the EBNA-1 p107 peptide, collagen, and keratin: Implications for the pathogenesis of rheumatoid arthritis. Clin Immunol Immunopathol 1990; 54: 14–25
  • Kouri T, Petersen J, Rhodes G, et al. Antibodies to synthetic peptides from Epstein–Barr nuclear antigen-1 in sera of patients with early rheumatoid arthritis and in preillness sera. J Rheumatol 1990; 17: 1442–1449
  • Baboonian C, Halliday D, Venables PJ, Pawlowski T, Millman G, Maini RN. Antibodies in rheumatoid arthritis react specifically with the glycine alanine repeat sequence of Epstein–Barr nuclear antigen-1. Rheumatol Int 1989; 9: 161–166
  • Petersen J, Rhodes G, Roudier J, Vaughan JH. Altered immune response to glycine-rich sequences of Epstein–Barr nuclear antigen-1 in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum 1990; 33: 993–1000
  • Roudier J, Petersen J, Rhodes GH, Luka J, Carson DA. Susceptibility to rheumatoid arthritis maps to a T-cell epitope shared by the HLA-Dw4 DR beta-1 chain and the Epstein–Barr virus glycoprotein gp110. Proc Natl Acad Sci USA 1989; 86: 5104–5108
  • Tosato G, Steinberg AD, Blaese RM. Defective EBV-specific suppressor T-cell function in rheumatoid arthritis. N Engl J Med 1981; 305: 1238–1243
  • Toussirot E, Wendling D, Tiberghien P, Luka J, Roudier J. Decreased T cell precursor frequencies to Epstein–Barr virus glycoprotein Gp110 in peripheral blood correlate with disease activity and severity in patients with rheumatoid arthritis. Ann Rheum Dis 2000; 59: 533–538
  • Klatt T, Ouyang Q, Flad T, et al. Expansion of peripheral CD8+and CD28- T cells in response to Epstein-Barr virus in patients with rheumatoid arthritis. J Rheumatol 2005; 32: 239–251
  • David-Ameline J, Lim A, Davodeau F, et al. Selection of T cells reactive against autologous B lymphoblastoid cells during chronic rheumatoid arthritis. J Immunol 1996; 157: 4697–4706
  • Scotet E, David-Ameline J, Peyrat MA, et al. T cell response to Epstein–Barr virus transactivators in chronic rheumatoid arthritis. J Exp Med 1996; 184: 1791–1800
  • Baeten D, Peene I, Union A, et al. Specific presence of intracellular citrullinated proteins in rheumatoid arthritis synovium: Relevance to antifilaggrin autoantibodies. Arthritis Rheum 2001; 44: 2255–2262
  • Pratesi F, Tommasi C, Anzilotti C, Chimenti D, Migliorini P. Deiminated Epstein–Barr virus nuclear antigen 1 is a target of anti-citrullinated protein antibodies in rheumatoid arthritis. Arthritis Rheum 2006; 54: 733–741
  • Schellekens GA, Visser H, de Jong BA, et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 2000; 43: 155–163
  • Rantapaa-Dahlqvist S, de Jong BA, Berglin E, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 2003; 48: 2741–2749
  • Agarwal V, Singh R, Chauhan S. Remission of rheumatoid arthritis after acute disseminated varicella-zoster infection. Clin Rheumatol 2007; 26: 779–780
  • Pomponi F, Cariati R, Zancai P, et al. Retinoids irreversibly inhibit in vitro growth of Epstein–Barr virus-immortalized B lymphocytes. Blood 1996; 88: 3147–3159
  • Wolf HJ, Morgan AJ. Epstein–Barr Virus vaccines. Herpesviruses and immunity, P Medveczky, H Friedman, M Bendinelli. Plenum Press, New York 1998; 231–246
  • Gu SY, Huang TM, Ruan L, et al. First EBV vaccine trial in humans using recombinant vaccinia virus expressing the major membrane antigen. Dev Biol Stand 1995; 84: 171–177
  • Jones PL, Wolffe AP. Relationships between chromatin organization and DNA methylation in determining gene expression. Semin Cancer Biol 1999; 9: 339–347
  • Robertson KD. DNA methylation, methyltransferases, and cancer. Oncogene 2001; 20: 3139–3155
  • Robertson KD. DNA methylation and chromatin—unraveling the tangled web. Oncogene 2002; 21: 5361–5379
  • Murray EJ, Grosveld F. Site specific demethylation in the promoter of human gamma-globin gene does not alleviate methylation mediated suppression. EMBO J 1987; 6: 2329–2335
  • Kintner C, Sugden B. Conservation and progressive methylation of Epstein–Barr viral DNA sequences in transformed cells. J Virol 1981; 38: 305–316
  • Dyson PJ, Farrell PJ. Chromatin structure of Epstein–Barr virus. J Gen Virol 1985; 66(Pt 9)1931–1940
  • Szyf M, Eliasson L, Mann V, Klein G, Razin A. Cellular and viral DNA hypomethylation associated with induction of Epstein–Barr virus lytic cycle. Proc Natl Acad Sci USA 1985; 82: 8090–8094
  • Masucci MG, Contreras-Salazar B, Ragnar E, et al. 5-Azacytidine upregulates the expression of Epstein–Barr virus nuclear antigen 2 (EBNA-2) through EBNA-6 and latent membrane protein in the Burkitt's lymphoma line Rael. J Virol 1989; 63: 3135–3141
  • Minarovits J, Minarovits-Kormuta S, Ehlin-Henriksson B, Falk K, Klein G, Ernberg I. Host cell phenotype-dependent methylation patterns of Epstein–Barr virus DNA. J Gen Virol 1991; 72: 1591–1599
  • Ernberg I, Falk K, Minarovits J, et al. The role of methylation in the phenotype-dependent modulation of Epstein–Barr nuclear antigen 2 and latent membrane protein genes in cells latently infected with Epstein–Barr virus. J Gen Virol 1989; 70: 2989–3002
  • Minarovits J, Hu LF, Marcsek Z, Minarovits-Kormuta S, Klein G, Ernberg I. RNA polymerase III-transcribed EBER 1 and 2 transcription units are expressed and hypomethylated in the major Epstein–Barr virus-carrying cell types. J Gen Virol 1992; 73: 1687–1692
  • Hu LF, Minarovits J, Cao SL, et al. Variable expression of latent membrane protein in nasopharyngeal carcinoma can be related to methylation status of the Epstein–Barr virus BNLF-1 5′-flanking region. J Virol 1991; 65: 1558–1567
  • Altiok E, Minarovits J, Hu LF, Contreras-Brodin B, Klein G, Ernberg I. Host-cell-phenotype-dependent control of the BCR2/BWR1 promoter complex regulates the expression of Epstein–Barr virus nuclear antigens 2–6. Proc Natl Acad Sci USA 1992; 89: 905–909
  • Honess RW, Gompels UA, Barrell BG, et al. Deviations from expected frequencies of CpG dinucleotides in herpesvirus DNAs may be diagnostic of differences in the states of their latent genomes. J Gen Virol 1989; 70(Pt 4)837–855
  • Robertson KD, Ambinder RF. Methylation of the Epstein–Barr virus genome in normal lymphocytes. Blood 1997; 90: 4480–4484
  • Paulson EJ, Speck SH. Differential methylation of Epstein–Barr virus latency promoters facilitates viral persistence in healthy seropositive individuals. J Virol 1999; 73: 9959–9968
  • Minarovits J. Epigenotypes of latent herpesvirus genomes. Curr Top Microbiol Immunol 2006; 310: 61–80
  • Li H, Minarovits J. Host cell-dependent expression of latent Epstein–Barr virus genomes: Regulation by DNA methylation. Adv Cancer Res 2003; 89: 133–156
  • Jones CH, Hayward SD, Rawlins DR. Interaction of the lymphocyte-derived Epstein–Barr virus nuclear antigen EBNA-1 with its DNA-binding sites. J Virol 1989; 63: 101–110
  • Li Q, Peterson KR, Fang X, Stamatoyannopoulos G. Locus control regions. Blood 2002; 100: 3077–3086
  • Salamon D, Takacs M, Myohanen S, Marcsek Z, Berencsi G, Minarovits J. De novo DNA methylation at nonrandom founder sites 5′ from an unmethylated minimal origin of DNA replication in latent Epstein–Barr virus genomes. Biol Chem 2000; 381: 95–105
  • Robertson KD, Ambinder RF. 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 1997; 71: 6445–6454
  • Zhou J, Chau CM, Deng Z, et al. Cell cycle regulation of chromatin at an origin of DNA replication. EMBO J 2005; 24: 1406–1417
  • Chau CM, Lieberman PM. Dynamic chromatin boundaries delineate a latency control region of Epstein–Barr virus. J Virol 2004; 78: 12308–12319
  • Day L, Chau CM, Nebozhyn M, Rennekamp AJ, Showe M, Lieberman PM. Chromatin profiling of Epstein–Barr virus latency control region. J Virol 2007; 81: 6389–6401
  • Fejer G, Koroknai A, Banati F, et al. Latency type specific distribution of epigenetic marks at the alternative promoters Cp and Qp of Epstein–Barr virus. J Gen Virol 2008 (In press).
  • Kirby H, Rickinson A, Bell A. The activity of the Epstein–Barr virus BamHI W promoter in B cells is dependent on the binding of CREB/ATF factors. J Gen Virol 2000; 81: 1057–1066
  • Tierney RJ, Kirby HE, Nagra JK, Desmond J, Bell AI, Rickinson AB. 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 2000; 74: 10468–10479
  • Jansson A, Masucci M, Rymo L. Methylation of discrete sites within the enhancer region regulates the activity of the Epstein–Barr virus BamHI W promoter in Burkitt lymphoma lines. J Virol 1992; 66: 62–69
  • Elliott J, Goodhew EB, Krug LT, Shakhnovsky N, Yoo L, Speck SH. Variable methylation of the Epstein–Barr virus Wp EBNA gene promoter in B-lymphoblastoid cell lines. J Virol 2004; 78: 14062–14065
  • Hutchings IA, Tierney RJ, Kelly GL, Stylianou J, Rickinson AB, Bell AI. Methylation status of the Epstein–Barr virus (EBV) BamHI W latent cycle promoter and promoter activity: Analysis with novel EBV-positive Burkitt and lymphoblastoid cell lines. J Virol 2006; 80: 10700–10711
  • Takacs M, Myohanen S, Altiok E, Minarovits J. Analysis of methylation patterns in the regulatory region of the latent Epstein–Barr virus promoter BCR2 by automated fluorescent genomic sequencing. Biol Chem 1998; 379: 417–422
  • Evans TJ, Jacquemin MG, Farrell PJ. Efficient EBV superinfection of group I Burkitt's lymphoma cells distinguishes requirements for expression of the Cp viral promoter and can activate the EBV productive cycle. Virology 1995; 206: 866–877
  • Schaefer BC, Strominger JL, Speck SH. Host-cell-determined methylation of specific Epstein–Barr virus promoters regulates the choice between distinct viral latency programs. Mol Cell Biol 1997; 17: 364–377
  • Robertson KD, Hayward SD, Ling PD, Samid D, Ambinder RF. 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 1995; 15: 6150–6159
  • Imai S, Koizumi S, Sugiura M, et al. Gastric carcinoma: Monoclonal epithelial malignant cells expressing Epstein–Barr virus latent infection protein. Proc Natl Acad Sci USA 1994; 91: 9131–9135
  • Robertson KD, Manns A, Swinnen LJ, Zong JC, Gulley ML, Ambinder RF. CpG methylation of the major Epstein–Barr virus latency promoter in Burkitt's lymphoma and Hodgkin's disease. Blood 1996; 88: 3129–3136
  • Tao Q, Robertson KD, Manns A, Hildesheim A, Ambinder RF. Epstein–Barr virus (EBV) in endemic Burkitt's lymphoma: Molecular analysis of primary tumor tissue. Blood 1998; 91: 1373–1381
  • Tao Q, Swinnen LJ, Yang J, Srivastava G, Robertson KD, Ambinder RF. Methylation status of the Epstein–Barr virus major latent promoter C in iatrogenic B cell lymphoproliferative disease. Application of PCR-based analysis. Am J Pathol 1999; 155: 619–625
  • Minarovits J, Hu LF, Minarovits-Kormuta S, Klein G, Ernberg I. Sequence-specific methylation inhibits the activity of the Epstein–Barr virus LMP 1 and BCR2 enhancer-promoter regions. Virology 1994; 200: 661–667
  • Tao Q, Robertson KD, Manns A, Hildesheim A, Ambinder RF. The Epstein–Barr virus major latent promoter Qp is constitutively active, hypomethylated, and methylation sensitive. J Virol 1998; 72: 7075–7083
  • Schaefer BC, Strominger JL, Speck SH. Redefining the Epstein–Barr virus-encoded nuclear antigen EBNA-1 gene promoter and transcription initiation site in group I Burkitt lymphoma cell lines. Proc Natl Acad Sci USA 1995; 92: 10565–10569
  • Tsai CN, Liu ST, Chang YS. Identification of a novel promoter located within the Bam HI Q region of the Epstein–Barr virus genome for the EBNA 1 gene. DNA Cell Biol 1995; 14: 767–776
  • Nonkwelo C, Skinner J, Bell A, Rickinson A, Sample J. Transcription start sites downstream of the Epstein–Barr virus (EBV) Fp promoter in early-passage Burkitt lymphoma cells define a fourth promoter for expression of the EBV EBNA-1 protein. J Virol 1996; 70: 623–627
  • Zetterberg H, Stenglein M, Jansson A, Ricksten A, Rymo L. 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 1999; 80: 457–466
  • Falk KI, Szekely L, Aleman A, Ernberg I. 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 1998; 72: 2969–2974
  • Takacs M, Salamon D, Myohanen S, et al. Epigenetics of latent Epstein–Barr virus genomes: High resolution methylation analysis of the bidirectional promoter region of latent membrane protein 1 and 2B genes. Biol Chem 2001; 382: 699–705
  • Salamon D, Takacs M, Schwarzmann F, Wolf H, Minarovits J, Niller HH. High-resolution methylation analysis and in vivo protein–DNA binding at the promoter of the viral oncogene LMP2A in B cell lines carrying latent Epstein–Barr virus genomes. Virus Genes 2003; 27: 57–66
  • Gerle B, Koroknai A, Fejer G, et al. Acetylated histone H3 and H4 mark the upregulated LMP2A-promoter of Epstein–Barr virus in lymphoid cells. J Gen Virol 2007;81:13242–13247.
  • Niller HH, Salamon D, Uhlig J, et al. Nucleoprotein structure of immediate-early promoters Zp and Rp and of oriLyt of latent Epstein–Barr virus genomes. J Virol 2002; 76: 4113–4118
  • Bhende PM, Seaman WT, Delecluse HJ, Kenney SC. BZLF1 activation of the methylated form of the BRLF1 immediate-early promoter is regulated by BZLF1 residue 186. J Virol 2005; 79: 7338–7348
  • Bhende PM, Seaman WT, Delecluse HJ, Kenney SC. The EBV lytic switch protein, Z, preferentially binds to and activates the methylated viral genome. Nat Genet 2004; 36: 1099–1104
  • Rajcani J, Durmanova V. Early expression of herpes simplex virus (HSV) proteins and reactivation of latent infection. Folia Microbiol (Praha) 2000; 45: 7–28
  • Valyi-Nagy T, Shukla D, Engelhard HH, Kavouras J, Scanlan P. Latency Strategies of Alphaherpesviruses. Latency strategies of herpesviruses, J Minarovits, E Gonczol, T Valyi-Nagy. Springer, New York 2007; 1–36
  • Marschall M, Alliger P, Schwarzmann F, et al. The lytic transition of Epstein-Barr virus is imitated by recombinant B cell. Arch Virol 1993; 129: 23–33
  • Rochford R, Mosier DE. Differential Epstein–Barr virus gene expression in B-cell subsets recovered from lymphomas in SCID mice after transplantation of human peripheral blood lymphocytes. J Virol 1995; 69: 150–155
  • Takada K, Ono Y. Synchronous and sequential activation of latently infected Epstein–Barr virus genomes. J Virol 1989; 63: 445–449
  • Greenspan JS, Greenspan D, Lennette ET, et al. Replication of Epstein–Barr virus within the epithelial cells of oral “hairy” leukoplakia, an AIDS-associated lesion. N Engl J Med 1985; 313: 1564–1571
  • Becker J, Leser U, Marschall M, et al. Expression of proteins encoded by Epstein–Barr virus trans-activator genes depends on the differentiation of epithelial cells in oral hairy leukoplakia. Proc Natl Acad Sci USA 1991; 88: 8332–8336
  • Rabanus JP, Greenspan D, Petersen V, Leser U, Wolf H, Greenspan JS. Subcellular distribution and life cycle of Epstein–Barr virus in keratinocytes of oral hairy leukoplakia. Am J Pathol 1991; 139: 185–197
  • Speck SH, Chatila T, Flemington E. Reactivation of Epstein–Barr virus: Regulation and function of the BZLF1 gene. Trends Microbiol 1997; 5: 399–405
  • Ben Sasson SA, Klein G. Activation of the Epstein–Barr virus genome by 5-aza-cytidine in latently infected human lymphoid lines. Int J Cancer 1981; 28: 131–135
  • Gradoville L, Kwa D, El Guindy A, Miller G. Protein kinase C-independent activation of the Epstein–Barr virus lytic cycle. J Virol 2002; 76: 5612–5626
  • Hsu CH, Hergenhahn M, Chuang SE, et al. Induction of Epstein–Barr virus (EBV) reactivation in Raji cells by doxorubicin and cisplatin. Anticancer Res 2002; 22: 4065–4071
  • Kudoh A, Fujita M, Zhang L, et al. Epstein–Barr virus lytic replication elicits ATM checkpoint signal transduction while providing an S-phase-like cellular environment. J Biol Chem 2005; 280: 8156–8163
  • Kamel OW, Weiss LM, vende Rijn M, Colby TV, Kingma DW, Jaffe ES. Hodgkin's disease and lymphoproliferations resembling Hodgkin's disease in patients receiving long-term low-dose methotrexate therapy. Am J Surg Pathol 1996; 20: 1279–1287
  • Menke DM, Griesser H, Moder KG, Tefferi A, Luthra HS, Cohen MD, Colon-Otero G, LLoyd RV. Lymphomas in patients with connective tissue disease. Comparison of p53 protein expression and latent EBV infection in patients immunosuppressed with methotrexate. Am J Clin Pathol 2000; 113: 212–218
  • Feng WH, Cohen JI, Fischer S, Li L, Sneller M, Goldbach-Mansky R, Rasb-Traub N, Delecluse HJ, Kenney SC. Reactivation of latent Epstein-Barr virus by methotrexate: a potential contributor to methotrexate-associated lymphomas. J Natl Cancer Inst 2004; 96: 1691–1702

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