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EBV Persistence—Introducing the Virus

  • David A. Thorley-LawsonEmail author
Chapter
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 390)

Abstract

Persistent infection by EBV is explained by the germinal center model (GCM) which provides a satisfying and currently the only explanation for EBVs disparate biology. Since the GCM touches on every aspect of the virus, this chapter will serve as an introduction to the subsequent chapters. EBV is B lymphotropic, and its biology closely follows that of normal mature B lymphocytes. The virus persists quiescently in resting memory B cells for the lifetime of the host in a non-pathogenic state that is also invisible to the immune response. To access this compartment, the virus infects naïve B cells in the lymphoepithelium of the tonsils and activates these cells using the growth transcription program. These cells migrate to the GC where they switch to a more limited transcription program, the default program, which helps rescue them into the memory compartment where the virus persists. For egress, the infected memory cells return to the lymphoepithelium where they occasionally differentiate into plasma cells activating viral replication. The released virus can either infect more naïve B cells or be amplified in the epithelium for shedding. This cycle of infection and the quiescent state in memory B cells allow for lifetime persistence at a very low level that is remarkably stable over time. Mathematically, this is a stable fixed point where the mechanisms regulating persistence drive the state back to equilibrium when perturbed. This is the GCM of EBV persistence. Other possible sites and mechanisms of persistence will also be discussed.

Keywords

Germinal Center Class Switch Recombination Growth Program Transcription Program Default Program 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

AID

Activation-induced cytidine deaminase

AIM

Acute infectious mononucleosis

APOBEC

Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like

BAFF

B cell activating factor

BCR

B cell receptor

BL

Burkitt’s lymphoma

BLC

B lymphocyte chemoattractant CXCL13

CD40L

CD40 ligand

cIg

Cytoplasmically expressed immunoglobulin

CPM

Cyclic pathogen model

CtBP

C-terminal-binding protein

CTL

Cytotoxic T cell

DZ

Dark zone

eBL

Endemic Burkitt’s lymphoma

EBV

Epstein-Barr virus

EBNA

Epstein-Barr virus nuclear antigen

GC

Germinal center

GCM

Germinal center model

HD

Hodgkin’s disease

HEV

High endothelial venules

HIV

Human immunodeficiency virus

IE

Immediate early

Ig

Immunoglobulin

IL

Immunoblastic lymphoma

LMP

Latent membrane protein

LZ

Light zone

RBPJk

Recombining binding protein

RTPCR

Real-time polymerase chain reaction

SDF1

Stromal cell-derived factor 1 CXCL12

sIg

Surface-expressed immunoglobulin

sBL

Sporadic Burkitt’s lymphoma

Th

CD4+ T helper cell

Notes

Acknowledgments

The work described here is in large part the consequence of research carried out by a number of graduate students in my own laboratory too numerous to mention individually but hopefully appropriately referenced in the text. I would also like to express my thanks to Michael Lawson for a very careful and thorough editing of the text. To the extent that this chapter is comprehendible, it is due to him. Finally, I would like to acknowledge NIH, who have supported my laboratory continuously through Public Health Service grants R01 CA65883 and R01 AI18757.

References

  1. Adams A, Lindahl T (1975) Epstein-Barr virus genomes with properties of circular DNA molecules in carrier cells. Proc Natl Acad Sci USA 72:1477–1481PubMedCentralPubMedCrossRefGoogle Scholar
  2. Allday MJ (2009) How does Epstein-Barr virus (EBV) complement the activation of Myc in the pathogenesis of Burkitt’s lymphoma? Semin Cancer Biol 19:366–376PubMedCentralPubMedCrossRefGoogle Scholar
  3. Allday MJ (2013) EBV finds a polycomb-mediated, epigenetic solution to the problem of oncogenic stress responses triggered by infection. Front Genet 4:212PubMedCentralPubMedCrossRefGoogle Scholar
  4. Allday MJ, Crawford DH, Griffin BE (1989) Epstein-Barr virus latent gene expression during the initiation of B cell immortalization. J Gen Virol 70:1755–1764PubMedCrossRefGoogle Scholar
  5. Allday MJ, Sinclair A, Parker G, Crawford DH, Farrell PJ (1995) Epstein-Barr virus efficiently immortalizes human B cells without neutralizing the function of p53. EMBO J 14:1382–1391PubMedCentralPubMedGoogle Scholar
  6. Allen CD, Ansel KM, Low C, Lesley R, Tamamura H, Fujii N, Cyster JG (2004) Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat Immunol 5:943–952PubMedCrossRefGoogle Scholar
  7. Ambinder RF (2007) Epstein-barr virus and hodgkin lymphoma. Hematol Am Soc Hematol Educ Program 2007:204–209Google Scholar
  8. Anagnostopoulos I, Hummel M, Kreschel C, Stein H (1995) Morphology, immunophenotype, and distribution of latently and/or productively Epstein-Barr virus-infected cells in acute infectious mononucleosis: implications for the interindividual infection route of Epstein-Barr virus. Blood 85:744–750PubMedGoogle Scholar
  9. Andersson-Anvret M, Forsby N, Klein G, Henle W (1977) Relationship between the Epstein-Barr virus and undifferentiated nasopharyngeal carcinoma: correlated nucleic acid hybridization and histopathological examination. Int J Cancer 20:486–494PubMedCrossRefGoogle Scholar
  10. Arrand JJ, Rymo L (1982) Characterisation of the major Epstein-Barr virus specific RNA in Burkitt lymphoma derived cells. J Virol 41:376–389PubMedCentralPubMedGoogle Scholar
  11. Artavanis-Tsakonas S, Matsuno K, Fortini ME (1995) Notch signaling. Science 268:225–232PubMedCrossRefGoogle Scholar
  12. Ascherio A, Munger KL (2010) 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: Epstein-Barr virus and multiple sclerosis: epidemiological evidence. Clin Exp Immunol 160:120–124PubMedCentralPubMedCrossRefGoogle Scholar
  13. Babcock GJ, Decker LL, Volk M, Thorley-Lawson DA (1998) EBV persistence in memory B cells in vivo. Immunity 9:395–404PubMedCrossRefGoogle Scholar
  14. Babcock GJ, Decker LL, Freeman RB, Thorley-Lawson DA (1999) Epstein-barr virus-infected resting memory B cells, not proliferating lymphoblasts, accumulate in the peripheral blood of immunosuppressed patients. J Exp Med 190:567–576PubMedCentralPubMedCrossRefGoogle Scholar
  15. Babcock GJ, Hochberg D, Thorley-Lawson AD (2000) The expression pattern of Epstein-Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity 13:497–506PubMedCrossRefGoogle Scholar
  16. Baichwal VR, Sugden B (1988) Transformation of Balb 3T3 cells by the BNLF-1 gene of Epstein-Barr virus. Oncogene 2:461–467PubMedGoogle Scholar
  17. Banchereau J, Bazan F, Blanchard D, Briere F, Galizzi JP, Van KC, Liu YJ, Rousset F, Saeland S (1994) The CD40 antigen and its ligand. Annu Rev Immunol 12:881–922PubMedCrossRefGoogle Scholar
  18. Barton E, Mandal P, Speck SH (2011) Pathogenesis and host control of gammaherpesviruses: lessons from the mouse. Annu Rev Immunol 29:351–397PubMedCrossRefGoogle Scholar
  19. Bassiri H, Janice YEO WC, Rothman J, Koretzky GA, Nichols KE (2008) X-linked lymphoproliferative disease (XLP): a model of impaired anti-viral, anti-tumor and humoral immune responses. Immunol Res 42:145–159Google Scholar
  20. Basso K, Dalla-Favera R (2010) BCL6: master regulator of the germinal center reaction and key oncogene in B cell lymphomagenesis. Adv Immunol 105:193–210PubMedCrossRefGoogle Scholar
  21. Beaufils P, Choquet D, Mamoun RZ, Malissen B (1993) The (YXXL/I)2 signalling motif found in the cytoplasmic segments of the bovine leukaemia virus envelope protein and Epstein-Barr virus latent membrane protein 2A can elicit early and late lymphocyte activation events. EMBO J 12:5105–5112PubMedCentralPubMedGoogle Scholar
  22. Bechtel D, Kurth J, Unkel C, Kuppers R (2005) 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 106:4345–4350PubMedCrossRefGoogle Scholar
  23. Bernasconi NL, Traggiai E, Lanzavecchia A (2002) Maintenance of serological memory by polyclonal activation of human memory B cells. Science 298:2199–2202PubMedCrossRefGoogle Scholar
  24. Birkenbach M, Josefsen K, Yalamanchili R, Lenoir G, Kieff E (1993) Epstein-Barr virus-induced genes: first lymphocyte-specific G protein-coupled peptide receptors. J Virol 67:2209–2220PubMedCentralPubMedGoogle Scholar
  25. Bonnet M, Guinebretiere JM, Kremmer E, Grunewald V, Benhamou E, Contesso G, Joab I (1999) Detection of Epstein-Barr virus in invasive breast cancers. J Natl Cancer Inst 91:1376–1381PubMedCrossRefGoogle Scholar
  26. Borza CM, Hutt-Fletcher LM (2002) Alternate replication in B cells and epithelial cells switches tropism of Epstein-Barr virus. Nat Med 8:594–599PubMedCrossRefGoogle Scholar
  27. Brandtzaeg P, Baekkevold ES, Farstad IN, Jahnsen FL, Johansen FE, Nilsen EM, Yamanaka T (1999a) Regional specialization in the mucosal immune system: what happens in the microcompartments? Immunol Today 20:141–151PubMedCrossRefGoogle Scholar
  28. Brandtzaeg P, Farstad IN, Haraldsen G (1999b) Regional specialization in the mucosal immune system: primed cells do not always home along the same track. Immunol Today 20:267–277PubMedCrossRefGoogle Scholar
  29. Calame KL, Lin KI, Tunyaplin C (2003) Regulatory mechanisms that determine the development and function of plasma cells. Annu Rev Immunol 21:205–230 Epub 2001 Dec 19PubMedCrossRefGoogle Scholar
  30. Caldwell RG, Wilson JB, Anderson SJ, Longnecker R (1998) Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity 9:405–411PubMedCrossRefGoogle Scholar
  31. Callan MF, Annels N, Steven N, Tan L, Wilson J, McMichael AJ, Rickinson AB (1998a) T cell selection during the evolution of CD8+ T cell memory in vivo. Eur J Immunol 28:4382–4390PubMedCrossRefGoogle Scholar
  32. Callan MF, Tan L, Annels N, Ogg GS, Wilson JD, O’Callaghan CA, Steven N, McMichael AJ, Rickinson AB (1998b) Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus In vivo. J Exp Med 187:1395–1402PubMedCentralPubMedCrossRefGoogle Scholar
  33. Carbone A, Gaidano G, Gloghini A, Larocca LM, Capello D, Canzonieri V, Antinori A, Tirelli U, Falini B, Dalla-Favera R (1998) Differential expression of BCL-6, CD138/syndecan-1, and Epstein-Barr virus-encoded latent membrane protein-1 identifies distinct histogenetic subsets of acquired immunodeficiency syndrome-related non-Hodgkin’s lymphomas. Blood 91:747–755PubMedGoogle Scholar
  34. Casola S, Otipoby KL, Alimzhanov M, Humme S, Uyttersprot N, Kutok JL, Carroll MC, Rajewsky K (2004a) B cell receptor signal strength determines B cell fate. Nat Immunol 5:317–327PubMedCrossRefGoogle Scholar
  35. Casola S, Otipoby KL, Alimzhanov M, Humme S, Uyttersprot N, Kutok JL, Carroll MC, Rajewsky K (2004b) B cell receptor signal strength determines B cell fate. Nat Immunol 5:317–327Google Scholar
  36. Catalina MD, Sullivan JL, Bak KR, Luzuriaga K (2001) Differential evolution and stability of epitope-specific CD8(+) T cell responses in EBV infection. J Immunol 167:4450–4457PubMedCrossRefGoogle Scholar
  37. Cattoretti G, Chang CC, Cechova K, Zhang J, Ye BH, Falini B, Louie DC, Offit K, Chaganti RS, Dalla-Favera R (1995) BCL-6 protein is expressed in germinal-center B cells. Blood 86:45–53PubMedGoogle Scholar
  38. Chaganti S, Heath EM, Bergler W, Kuo M, Buettner M, Niedobitek G, Rickinson AB, Bell AI (2009) Epstein-Barr virus colonization of tonsillar and peripheral blood B-cell subsets in primary infection and persistence. Blood 113:6372–6381PubMedCrossRefGoogle Scholar
  39. Chang RA, Miller SD, Longnecker R (2012) Epstein-Barr virus latent membrane protein 2A exacerbates experimental autoimmune encephalomyelitis and enhances antigen presentation function. Sci Rep 2:353PubMedCentralPubMedCrossRefGoogle Scholar
  40. Chatterjee B, Leung CS, Munz C (2014) Animal models of Epstein Barr virus infection. J Immunol Methods 40:80–87Google Scholar
  41. Chen F, Zou JZ, Di RL, Winberg G, Hu LF, Klein E, Klein G, Ernberg I (1995) A subpopulation of normal B cells latently infected with Epstein-Barr virus resembles Burkitt lymphoma cells in expressing EBNA-1 but not EBNA-2 or LMP1. J Virol 69:3752–3758PubMedCentralPubMedGoogle Scholar
  42. Chiang AK, Tao Q, Srivastava G, Ho FC (1996) Nasal NK- and T-cell lymphomas share the same type of Epstein-Barr virus latency as nasopharyngeal carcinoma and Hodgkin’s disease. Int J Cancer 68:285–290PubMedCrossRefGoogle Scholar
  43. Clute SC, Naumov YN, Watkin LB, Aslan N, Sullivan JL, Thorley-Lawson DA, Luzuriaga K, Welsh RM, Puzone R, Celada F, Selin LK (2010) Broad cross-reactive TCR repertoires recognizing dissimilar Epstein-Barr and influenza A virus epitopes. J Immunol 185:6753–6764PubMedCentralPubMedCrossRefGoogle Scholar
  44. Coffey AJ, Brooksbank RA, Brandau O, Oohashi T, Howell GR, Bye JM, Cahn AP, Durham J, Heath P, Wray P, Pavitt R, Wilkinson J, Leversha M, Huckle E, Shaw-Smith CJ, Dunham A, Rhodes S, Schuster V, Porta G, Yin L, Serafini P, Sylla B, Zollo M, Franco B, Bentley DR et al (1998) Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet 20:129–135PubMedCrossRefGoogle Scholar
  45. Collins CM, Speck SH (2014) Expansion of murine gammaherpesvirus latently infected B cells requires T follicular help. PLoS Pathog 10:e1004106PubMedCentralPubMedCrossRefGoogle Scholar
  46. Crotty S, Kersh EN, Cannons J, Schwartzberg PL, Ahmed R (2003) SAP is required for generating long-term humoral immunity. Nature 421:282–287PubMedCrossRefGoogle Scholar
  47. Daskalogianni C, Pyndiah S, Apcher S, Mazars A, Manoury B, Ammari N, Nylander K, Voisset C, Blondel M, Fahraeus R (2014) Epstein-Barr virus-encoded EBNA1 and ZEBRA: targets for therapeutic strategies against EBV-carrying cancers. J Pathol 235:334–341CrossRefGoogle Scholar
  48. Deacon EM, Pallesen G, Niedobitek G, Crocker J, Brooks L, Rickinson AB, Young LS (1993) Epstein-Barr virus and Hodgkin’s disease: transcriptional analysis of virus latency in the malignant cells. J Exp Med 177:339–349PubMedCrossRefGoogle Scholar
  49. Decker LL, Klaman LD, Thorley-Lawson DA (1996) Detection of the latent form of Epstein-Barr virus DNA in the peripheral blood of healthy individuals. J Virol 70:3286–3289PubMedCentralPubMedGoogle Scholar
  50. Decker LL, Babcock GJ, Thorley-Lawson DA (2001) Detection and discrimination of latent and replicative herpesvirus infection at the single cell level in vivo. Methods Mol Biol 174:111–116PubMedGoogle Scholar
  51. Delecluse HJ, Hammerschmidt W (2000) The genetic approach to the Epstein-Barr virus: from basic virology to gene therapy. Mol Pathol 53:270–279PubMedCentralPubMedCrossRefGoogle Scholar
  52. Delgado-Eckert E, Shapiro M (2011) A model of host response to a multi-stage pathogen. J Math Biol 63:201–227PubMedCentralPubMedCrossRefGoogle Scholar
  53. de-Thé G (1985) Epstein-Barr virus and Burkitt’s lymphoma worldwide: the causal relationship revisited. In: Olweny CLM, Lenoir GM, O’conor GT (eds) Burkitt’s Lymphoma a human cancer model. Oxford University Press, New YorkGoogle Scholar
  54. Dominguez-Sola D, Victora GD, Ying CY, Phan RT, Saito M, Nussenzweig MC, Dalla-Favera R (2012) The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry. Nat Immunol 13:1083–1091PubMedCentralPubMedCrossRefGoogle Scholar
  55. Dono M, Zupo S, Colombo M, Massara R, Gaidano G, Taborelli G, Ceppa P, Burgio VL, Chiorazzi N, Ferrarini M (2003) The human marginal zone B cell. Ann N Y Acad Sci 987:117–124PubMedCrossRefGoogle Scholar
  56. Dupre L, Andolfi G, Tangye SG, Clementi R, Locatelli F, Arico M, Aiuti A, Roncarolo MG (2005) SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells. Blood 105:4383–4389PubMedCrossRefGoogle Scholar
  57. Edson CM, Thorley-Lawson DA (1981) Epstein-Barr virus membrane antigens: characterization, distribution, and strain differences. J Virol 39:172–184PubMedCentralPubMedGoogle Scholar
  58. Ehlin-Henriksson B, Zou JZ, Klein G, Ernberg I (1999) Epstein-Barr virus genomes are found predominantly in IgA-positive B cells in the blood of healthy carriers. Int J Cancer 83:50–54PubMedCrossRefGoogle Scholar
  59. Faulkner GC, Burrows SR, Khanna R, Moss DJ, Bird AG, Crawford DH (1999) X-Linked agammaglobulinemia patients are not infected with Epstein-Barr virus: implications for the biology of the virus. J Virol 73:1555–1564PubMedCentralPubMedGoogle Scholar
  60. Fingeroth JD, Weis JJ, Tedder TF, Strominger JL, Biro PA, Fearon DT (1984) Epstein-Barr virus receptor of human B lymphocytes is the C3d receptor CR2. Proc Natl Acad Sci USA 81:4510–4514PubMedCentralPubMedCrossRefGoogle Scholar
  61. Fox RI, Chilton T, Scott S, Benton L, Howell FV, Vaughan JH (1987) Potential role of Epstein-Barr virus in Sjogren’s syndrome. Rheum Dis Clin North Am 13:275–292PubMedGoogle Scholar
  62. Gatto D, Brink R (2013) B cell localization: regulation by EBI2 and its oxysterol ligand. Trends Immunol 34:336–341PubMedCrossRefGoogle Scholar
  63. Gires O, Zimber-Strobl U, Gonnella R, Ueffing M, Marschall G, Zeidler R, Pich D, Hammerschmidt W (1997) Latent membrane protein 1 of Epstein-Barr virus mimics a constitutively active receptor molecule. EMBO J 16:6131–6140PubMedCentralPubMedCrossRefGoogle Scholar
  64. Glaser SL, Lin RJ, Stewart SL, Ambinder RF, Jarrett RF, Brousset P, Pallesen G, Gulley ML, Khan G, O’Grady J, Hummel M, Preciado MV, Knecht H, Chan JK, Claviez A (1997) Epstein-Barr virus-associated Hodgkin’s disease: epidemiologic characteristics in international data. Int J Cancer 70:375–382PubMedCrossRefGoogle Scholar
  65. Golden HD, Chang RS, Prescott W, Simpson E, Cooper TY (1973) Leukocyte-transforming agent: prolonged excretion by patients with mononucleosis and excretion by normal individuals. J Infect Dis 127:471–473PubMedCrossRefGoogle Scholar
  66. Gratama JW, Oosterveer MA, Zwaan FE, Lepoutre J, Klein G, Ernberg I (1988) Eradication of Epstein-Barr virus by allogeneic bone marrow transplantation: implications for sites of viral latency. Proc Natl Acad Sci USA 85:8693–8696PubMedCentralPubMedCrossRefGoogle Scholar
  67. Gray D, Maclennan IC, Bazin H, Khan M (1982) Migrant mu+ delta+ and static mu+ delta-B lymphocyte subsets. Eur J Immunol 12:564–569PubMedCrossRefGoogle Scholar
  68. Greenspan JS, Greenspan D, Lennette ET, Abrams DI, Conant MA, Petersen V, Freese UK (1985) Replication of Epstein-Barr virus within the epithelial cells of oral “hairy” leukoplakia, an AIDS-associated lesion. N Engl J Med 313:1564–1571PubMedCrossRefGoogle Scholar
  69. Gregory CD, Tursz T, Edwards CF, Tetaud C, Talbot M, Caillou B, Rickinson AB, Lipinski M (1987) Identification of a subset of normal B cells with a Burkitt’s lymphoma (BL)-like phenotype. J Immunol 139:313–318PubMedGoogle Scholar
  70. Gregory CD, Rowe M, Rickinson AB (1990) Different Epstein-Barr virus-B cell interactions in phenotypically distinct clones of a Burkitt’s lymphoma cell line. J Gen Virol 71:1481–1495PubMedCrossRefGoogle Scholar
  71. Gross AJ, Hochberg D, Rand WM, Thorley-Lawson DA (2005) EBV and systemic lupus erythematosus: a new perspective. J Immunol 174:6599–6607PubMedCrossRefGoogle Scholar
  72. Gulley ML, Raphael M, Lutz CT, Ross DW, Raab-Traub N (1992) Epstein-Barr virus integration in human lymphomas and lymphoid cell lines. Cancer 70:185–191PubMedCrossRefGoogle Scholar
  73. Hadinoto V, Shapiro M, Greenough TC, Sullivan JL, Luzuriaga K, Thorley-Lawson DA (2008) On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis. Blood 111:1420–1427PubMedCentralPubMedCrossRefGoogle Scholar
  74. Hadinoto V, Shapiro M, Sun CC, Thorley-Lawson DA (2009) The dynamics of EBV shedding implicate a central role for epithelial cells in amplifying viral output. PLoS Pathog 5:e1000496PubMedCentralPubMedCrossRefGoogle Scholar
  75. Hardy R (2008) Chapter 7: B Lymphocyte Development and Biology. Fundamental Immunology, 6th edn. Lippincott Williams and Wilkins, PhiladelphiaGoogle Scholar
  76. Hawkins JB, Delgado-Eckert E, Thorley-Lawson DA, Shapiro M (2013) The cycle of EBV infection explains persistence, the sizes of the infected cell populations and which come under CTL regulation. PLoS Pathog 9:e1003685PubMedCentralPubMedCrossRefGoogle Scholar
  77. He B, Raab-Traub N, Casali P, Cerutti A (2003) EBV-encoded latent membrane protein 1 cooperates with BAFF/BLyS and APRIL to induce T cell-independent Ig heavy chain class switching. J Immunol 171:5215–5224PubMedCrossRefPubMedCentralGoogle Scholar
  78. Heath E, Begue-Pastor N, Chaganti S, Croom-Carter D, Shannon-Lowe C, Kube D, Feederle R, Delecluse HJ, Rickinson AB, Bell AI (2012) Epstein-Barr virus infection of naive B cells in vitro frequently selects clones with mutated immunoglobulin genotypes: implications for virus biology. PLoS Pathog 8:e1002697PubMedCentralPubMedCrossRefGoogle Scholar
  79. Henderson S, Rowe M, Gregory C, Croom-Carter D, Wang F, Longnecker R, Kieff E, Rickinson A (1991) Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell 65:1107–1115PubMedCrossRefGoogle Scholar
  80. Henderson S, Huen D, Rowe M, Dawson C, Johnson G, Rickinson A (1993) Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death. Proc Natl Acad Sci USA 90:8479–8483PubMedCentralPubMedCrossRefGoogle Scholar
  81. Henle W, Henle G (1979) Seroepidemiology of the virus. In: Epstein MA, Achong BG (eds) The Epstein-Barr virus. Springer, BerlinGoogle Scholar
  82. Henle W, Diehl V, Kohn G, Zur Hausen H, Henle G (1967) Herpes-type virus and chromosome marker in normal leukocytes after growth with irradiated Burkitt cells. Science 157:1064–1065Google Scholar
  83. Herbst H, Dallenbach F, Hummel M, Niedobitek G, Pileri S, Muller LN, Stein H (1991) Epstein-Barr virus latent membrane protein expression in Hodgkin and Reed-Sternberg cells. Proc Natl Acad Sci USA 88:4766–4770PubMedCentralPubMedCrossRefGoogle Scholar
  84. Hickabottom M, Parker GA, Freemont P, Crook T, Allday MJ (2002) Two nonconsensus sites in the Epstein-Barr virus oncoprotein EBNA3A cooperate to bind the co-repressor carboxyl-terminal-binding protein (CtBP). J Biol Chem 277:47197–47204 (Epub 2002 Oct 7)PubMedCrossRefGoogle Scholar
  85. Hislop AD, Kuo M, Drake-Lee AB, Akbar AN, Bergler W, Hammerschmitt N, Khan N, Palendira U, Leese AM, Timms JM, Bell AI, Buckley CD, Rickinson AB (2005) Tonsillar homing of Epstein-Barr virus-specific CD8+ T cells and the virus-host balance. J Clin Invest 115:2546–2555PubMedCentralPubMedCrossRefGoogle Scholar
  86. Hjalgrim H, Smedby KE, Rostgaard K, Molin D, Hamilton-Dutoit S, Chang ET, Ralfkiaer E, Sundstrom C, Adami HO, Glimelius B, Melbye M (2007) Infectious mononucleosis, childhood social environment, and risk of Hodgkin lymphoma. Cancer Res 67:2382–2388PubMedCrossRefGoogle Scholar
  87. Hoagland RJ (1955) The transmission of infectious mononucleosis. Am J Med Sci 229:262–272PubMedCrossRefGoogle Scholar
  88. Hoagland RJ (1964) The incubation period of infectious mononucleosis. Am J Public Health Nations Health 54:1699–1705PubMedCentralPubMedCrossRefGoogle Scholar
  89. Hoagland RJ (1967) Infectious mononucleosis. Infectious mononucleosis. Grune and Stratton Inc, New York/LondonGoogle Scholar
  90. Hochberg DR, Thorley-Lawson DA (2005) Quantitative detection of viral gene expression in populations of Epstein-Barr virus-infected cells in vivo. Methods Mol Biol 292:39–56PubMedGoogle Scholar
  91. Hochberg D, Middeldorp JM, Catalina M, Sullivan JL, Luzuriaga K, Thorley-Lawson DA (2003a) Demonstration of the Burkitt’s Lymphoma Epstein-Barr virus phenotype in dividing latently infected memory cells in vivo. Proc Natl Acad Sci USA 101:239–244PubMedCentralPubMedCrossRefGoogle Scholar
  92. Hochberg D, Vorobyova T, Catalina M, Sullivan JS, Luzuriaga K, Thorley-Lawson DA (2003b) Acute infection with Epstein-Bar virus targets and overwhelms the memory B cell compartment with latently infected cells (Submitted)Google Scholar
  93. Hochberg D, Souza T, Catalina M, Sullivan JL, Luzuriaga K, Thorley-Lawson DA (2004) Acute infection with Epstein-Bar virus targets and overwhelms the peripheral memory B cell compartment with resting, latently infected cells. J Virol (in press)Google Scholar
  94. Hopwood P, Crawford DH (2000) The role of EBV in post-transplant malignancies: a review. J Clin Pathol 53:248–254PubMedCentralPubMedCrossRefGoogle Scholar
  95. Hoshino Y, Katano H, Zou P, Hohman P, Marques A, Tyring SK, Follmann D, Cohen JI (2009) Long-term administration of valacyclovir reduces the number of Epstein-Barr virus (EBV)-infected B cells but not the number of EBV DNA copies per B cell in healthy volunteers. J Virol 83:11857–11861PubMedCentralPubMedCrossRefGoogle Scholar
  96. Hurley EA, Thorley-Lawson DA (1988) B cell activation and the establishment of Epstein-Barr virus latency. J Exp Med 168:2059–2075PubMedCrossRefGoogle Scholar
  97. Inman GJ, Binne UK, Parker GA, Farrell PJ, Allday MJ (2001) Activators of the Epstein-Barr virus lytic program concomitantly induce apoptosis, but lytic gene expression protects from cell death. J Virol 75:2400–2410PubMedCentralPubMedCrossRefGoogle Scholar
  98. Iwakiri D (2014) Epstein-Barr virus-encoded RNAs: key molecules in viral pathogenesis. Cancers (Basel) 6:1615–1630CrossRefGoogle Scholar
  99. Izumi KM, Kieff ED (1997) The Epstein-Barr virus oncogene product latent membrane protein 1 engages the tumor necrosis factor receptor-associated death domain protein to mediate B lymphocyte growth transformation and activate NF- kappaB. Proc Natl Acad Sci USA 94:12592–12597PubMedCentralPubMedCrossRefGoogle Scholar
  100. James JA, Kaufman KM, Farris AD, Taylor-Albert E, Lehman TJ, Harley JB (1997) An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus. J Clin Invest 100:3019–3026PubMedCentralPubMedCrossRefGoogle Scholar
  101. Joseph AM, Babcock GJ, Thorley-Lawson DA (2000a) Cells expressing the Epstein-Barr virus growth program are present in and restricted to the naive B-cell subset of healthy tonsils. J Virol 74:9964–9971PubMedCentralPubMedCrossRefGoogle Scholar
  102. Joseph AM, Babcock GJ, Thorley-Lawson DA (2000b) EBV persistence involves strict selection of latently infected B cells. J Immunol 165:2975–2981PubMedCrossRefGoogle Scholar
  103. Kaiser C, Laux G, Eick D, Jochner N, Bornkamm GW, Kempkes B (1999) The proto-oncogene c-myc is a direct target gene of Epstein-Barr virus nuclear antigen 2. J Virol 73:4481–4484PubMedCentralPubMedGoogle Scholar
  104. Kantor AB (1991) The development and repertoire of B-1 cells (CD5 B cells). Immunol Today 12:389–391PubMedCrossRefGoogle Scholar
  105. Kempkes B, Spitkovsky D, Jansen-Durr P, Ellwart JW, Kremmer E, Delecluse HJ, Rottenberger C, Bornkamm GW, Hammerschmidt W (1995) B-cell proliferation and induction of early G1-regulating proteins by Epstein-Barr virus mutants conditional for EBNA2. EMBO J 14:88–96PubMedCentralPubMedGoogle Scholar
  106. Kennedy G, Komano J, Sugden B (2003) Epstein-Barr virus provides a survival factor to Burkitt’s lymphomas. Proc Natl Acad Sci USA 100:14269–14274PubMedCentralPubMedCrossRefGoogle Scholar
  107. Kenney SC, Mertz JE (2014) Regulation of the latent-lytic switch in Epstein-Barr virus. Semin Cancer Biol 26:60–68PubMedCrossRefGoogle Scholar
  108. Khan G, Miyashita EM, Yang B, Babcock GJ, Thorley-Lawson DA (1996) Is EBV persistence in vivo a model for B cell homeostasis? Immunity 5:173–179PubMedCrossRefGoogle Scholar
  109. Khanna R, Burrows SR, Neisig A, Neefjes J, Moss DJ, Silins SL (1997) Hierarchy of Epstein-Barr virus-specific cytotoxic T-cell responses in individuals carrying different subtypes of an HLA allele: implications for epitope-based antiviral vaccines. J Virol 71:7429–7435PubMedCentralPubMedGoogle Scholar
  110. Kieff E, Rickinson AB (2007) Epstein-Barr virus and its replication. In: Knipe DM, Howley PM (eds) Fields virology, 5th edn. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  111. Kirchmaier AL, Sugden B (1995) Plasmid maintenance of derivatives of oriP of Epstein-Barr virus. J Virol 69:1280–1283PubMedCentralPubMedGoogle Scholar
  112. Kis LL, Takahara M, Nagy N, Klein G, Klein E (2006) Cytokine mediated induction of the major Epstein-Barr virus (EBV)-encoded transforming protein, LMP-1. Immunol Lett 104:83–88PubMedCrossRefGoogle Scholar
  113. Kis LL, Salamon D, Persson EK, Nagy N, Scheeren FA, Spits H, Klein G, Klein E (2010) IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter. Proc Natl Acad Sci USA 107:872–877PubMedCentralPubMedCrossRefGoogle Scholar
  114. Kitano M, Moriyama S, Ando Y, Hikida M, Mori Y, Kurosaki T, Okada T (2011) Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity. Immunity 34:961–972PubMedCrossRefGoogle Scholar
  115. Klein G (1983) Specific chromosomal translocations and the genesis of B-cell-derived tumors in mice and men. Cell 32:311–315PubMedCrossRefGoogle Scholar
  116. Klein U, Klein G, Ehlin-Henriksson B, Rajewsky K, Kuppers R (1995) Burkitt’s lymphoma is a malignancy of mature B cells expressing somatically mutated V region genes. Mol Med 1:495–505PubMedCentralPubMedGoogle Scholar
  117. Klein U, Rajewsky K, Kuppers R (1998) Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J Exp Med 188:1679–1689PubMedCentralPubMedCrossRefGoogle Scholar
  118. Knight JS, Lan K, Subramanian C, Robertson ES (2003) Epstein-Barr virus nuclear antigen 3C recruits histone deacetylase activity and associates with the corepressors mSin3A and NCoR in human B-cell lines. J Virol 77:4261–4272PubMedCentralPubMedCrossRefGoogle Scholar
  119. Knowles DM, Cesarman E, Chadburn A, Frizzera G, Chen J, Rose EA, Michler RE (1995) Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. Blood 85:552–565PubMedGoogle Scholar
  120. Kovalchuk AL, Qi CF, Torrey TA, Taddesse-Heath L, Feigenbaum L, Park SS, Gerbitz A, Klobeck G, Hoertnagel K, Polack A, Bornkamm GW, Janz S, III Morse HC (2000) Burkitt lymphoma in the mouse. J Exp Med 192:1183–1190PubMedCentralPubMedCrossRefGoogle Scholar
  121. Kulwichit W, Edwards RH, Davenport EM, Baskar JF, Godfrey V, Raab-Traub N (1998) Expression of the Epstein-Barr virus latent membrane protein 1 induces B cell lymphoma in transgenic mice. Proc Natl Acad Sci USA 95:11963–11968PubMedCentralPubMedCrossRefGoogle Scholar
  122. Kuppers R (2012) New insights in the biology of Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program 2012:328–334PubMedGoogle Scholar
  123. Kuppers R, Rajewsky K (1998) The origin of Hodgkin and Reed/Sternberg cells in Hodgkin’s disease. Annu Rev Immunol 16:471–493PubMedCrossRefGoogle Scholar
  124. Kurosaki T (1999) Genetic analysis of B cell antigen receptor signaling. Annu Rev Immunol 17:555–592PubMedCrossRefGoogle Scholar
  125. Kurth J, Spieker T, Wustrow J, Strickler GJ, Hansmann LM, Rajewsky K, Kuppers R (2000) EBV-infected B cells in infectious mononucleosis: viral strategies for spreading in the B cell compartment and establishing latency. Immunity 13:485–495PubMedCrossRefGoogle Scholar
  126. Kurth J, Hansmann ML, Rajewsky K, Kuppers R (2003) 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 100:4730–4735PubMedCentralPubMedCrossRefGoogle Scholar
  127. Kuzembayeva M, Hayes M, Sugden B (2014) Multiple functions are mediated by the miRNAs of Epstein-Barr virus. Curr Opin Virol 7C:61–65CrossRefGoogle Scholar
  128. Laichalk LL, Thorley-Lawson DA (2005) Terminal differentiation into plasma cells initiates the replicative cycle of Epstein-Barr virus in vivo. J Virol 79:1296–1307PubMedCentralPubMedCrossRefGoogle Scholar
  129. Laichalk LL, Hochberg D, Babcock GJ, Freeman RB, Thorley-Lawson DA (2002) The dispersal of mucosal memory B cells: evidence from persistent EBV infection. Immunity 16:745–754PubMedCrossRefGoogle Scholar
  130. Lam N, Sugden B (2003) CD40 and its viral mimic, LMP1: similar means to different ends. Cell Signal 15:9–16PubMedCrossRefGoogle Scholar
  131. Lam KP, Kuhn R, Rajewsky K (1997) In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 90:1073–1083PubMedCrossRefGoogle Scholar
  132. Leder P (1985) Translocations among antibody genes in human cancer. In: Lenoir GM, O’conor GT, Olweny CLM (eds) Burkitt’s Lymphomaa human cancer model. Oxford University Press, New YorkGoogle Scholar
  133. Levitskaya J, Coram M, Levitsky V, Imreh S, Steigerwald MP, Klein G, Kurilla MG, Masucci MG (1995) Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature 375:685–688PubMedCrossRefGoogle Scholar
  134. Levitskaya J, Sharipo A, Leonchiks A, Ciechanover A, Masucci MG (1997) 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 94:12616–12621PubMedCentralPubMedCrossRefGoogle Scholar
  135. Li Q, Spriggs MK, Kovats S, Turk SM, Comeau MR, Nepom B, Hutt-Fletcher LM (1997) Epstein-Barr virus uses HLA class II as a cofactor for infection of B lymphocytes. J Virol 71:4657–4662PubMedCentralPubMedGoogle Scholar
  136. Liu YJ, Arpin C (1997) Germinal center development. Immunol Rev 156:111–126PubMedCrossRefGoogle Scholar
  137. Lotz M, Roudier J (1989) Epstein-Barr virus and rheumatoid arthritis: cellular and molecular aspects. Rheumatol Int 9:147–152PubMedGoogle Scholar
  138. Ma CS, Pittaluga S, Avery DT, Hare NJ, Maric I, Klion AD, Nichols KE, Tangye SG (2006) Selective generation of functional somatically mutated IgM+ CD27+, but not Ig isotype-switched, memory B cells in X-linked lymphoproliferative disease. J Clin Invest 116:322–333PubMedCentralPubMedCrossRefGoogle Scholar
  139. Macallan DC, Wallace DL, Zhang Y, Ghattas H, Asquith B, de Lara C, Worth A, Panayiotakopoulos G, Griffin GE, Tough DF, Beverley PC (2005) B-cell kinetics in humans: rapid turnover of peripheral blood memory cells. Blood 105:3633–3640PubMedCrossRefGoogle Scholar
  140. Mackay F, Schneider P (2009) Cracking the BAFF code. Nat Rev Immunol 9:491–502PubMedCrossRefGoogle Scholar
  141. Maclennan IC (1994) Germinal centers. Annu Rev Immunol 12:117–139PubMedCrossRefGoogle Scholar
  142. Maclennan IC (1998) B-cell receptor regulation of peripheral B cells. Curr Opin Immunol 10:220–225PubMedCrossRefGoogle Scholar
  143. Mancao C, Hammerschmidt W (2007) Epstein-Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival. Blood 110:3715–3721PubMedCentralPubMedCrossRefGoogle Scholar
  144. Manolov G, Manolova Y (1972) Marker band in one chromosome 14 from Burkitt lymphomas. Nature 237:33–34PubMedCrossRefGoogle Scholar
  145. Martinez-Valdez H, Guret C, de Bouteiller O, Fugier I, Banchereau J, Liu YJ (1996) Human germinal center B cells express the apoptosis-inducing genes Fas, c-myc, P53, and Bax but not the survival gene bcl-2. J Exp Med 183:971–977PubMedCrossRefGoogle Scholar
  146. Maruyama M, Lam KP, Rajewsky K (2000) Memory B-cell persistence is independent of persisting immunizing antigen. Nature 407:636–642PubMedCrossRefGoogle Scholar
  147. Matsumoto AK, Martin DR, Carter RH, Klickstein LB, Ahearn JM, Fearon DT (1993) Functional dissection of the CD21/CD19/TAPA-1/Leu-13 complex of B lymphocytes. J Exp Med 178:1407–1417PubMedCrossRefGoogle Scholar
  148. Miller CL, Burkhardt AL, Lee JH, Stealey B, Longnecker R, Bolen JB, Kieff E (1995) Integral membrane protein 2 of Epstein-Barr virus regulates reactivation from latency through dominant negative effects on protein-tyrosine kinases. Immunity 2:155–166PubMedCrossRefGoogle Scholar
  149. Miyashita EM, Yang B, Lam KM, Crawford DH, Thorley-Lawson DA (1995) A novel form of Epstein-Barr virus latency in normal B cells in vivo. Cell 80:593–601PubMedCrossRefGoogle Scholar
  150. Miyashita EM, Yang B, Babcock GJ, Thorley-Lawson DA (1997) Identification of the site of Epstein-Barr virus persistence in vivo as a resting B cell. J Virol 71:4882–4891PubMedCentralPubMedGoogle Scholar
  151. Moorthy R, Thorley-Lawson DA (1992) Mutational analysis of the transforming function of the EBV encoded LMP-1. Curr Top Microbiol Immunol 182:359–365PubMedGoogle Scholar
  152. Mosialos G, Birkenbach M, Yalamanchili R, Vanarsdale T, Ware C, Kieff E (1995) The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80:389–399PubMedCrossRefGoogle Scholar
  153. Muramatsu M, Nagaoka H, Shinkura R, Begum NA, Honjo T (2007) Discovery of activation-induced cytidine deaminase, the engraver of antibody memory. Adv Immunol 94:1–36PubMedCrossRefGoogle Scholar
  154. Nanbo A, Sugden A, Sugden B (2007) The coupling of synthesis and partitioning of EBV’s plasmid replicon is revealed in live cells. EMBO J 26:4252–4262PubMedCentralPubMedCrossRefGoogle Scholar
  155. Nemerow GR, Wolfert R, McNaughton ME, Cooper NR (1985) Identification and characterization of the Epstein-Barr virus receptor on human B lymphocytes and its relationship to the C3d complement receptor (CR2). J Virol 55:347–351PubMedCentralPubMedGoogle Scholar
  156. Nicholson LJ, Hopwood P, Johannessen I, Salisbury JR, Codd J, Thorley-Lawson D, Crawford DH (1997) Epstein-Barr virus latent membrane protein does not inhibit differentiation and induces tumorigenicity of human epithelial cells. Oncogene 15:275–283PubMedCrossRefGoogle Scholar
  157. Niedobitek G, Kremmer E, Herbst H, Whitehead L, Dawson CW, Niedobitek E, von Ostau C, Rooney N, Grasser FA, Young LS (1997) Immunohistochemical detection of the Epstein-Barr virus-encoded latent membrane protein 2A in Hodgkin’s disease and infectious mononucleosis. Blood 90:1664–1672PubMedGoogle Scholar
  158. Niedobitek G, Agathanggelou A, Steven N, Young LS (2000) Epstein-Barr virus (EBV) in infectious mononucleosis: detection of the virus in tonsillar B lymphocytes but not in desquamated oropharyngeal epithelial cells. Mol Pathol 53:37–42PubMedCentralPubMedCrossRefGoogle Scholar
  159. Nikitin PA, Yan CM, Forte E, Bocedi A, Tourigny JP, White RE, Allday MJ, Patel A, Dave SS, Kim W, Hu K, Guo J, Tainter D, Rusyn E, Luftig MA (2010) An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells. Cell Host Microbe 8:510–522PubMedCentralPubMedCrossRefGoogle Scholar
  160. Nilsson K (1979) The nature of lymphoid cell lines and their relationship to the virus. In: Epstein MA, Achong BG (eds) The Epstein-Barr virus. Springer, BerlinGoogle Scholar
  161. Nonkwelo C, Skinner J, Bell A, Rickinson A, Sample J (1996) 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 70:623–627PubMedCentralPubMedGoogle Scholar
  162. O’Nions J, Allday MJ (2003) Epstein-Barr virus can inhibit genotoxin-induced G1 arrest downstream of p53 by preventing the inactivation of CDK2. Oncogene 22:7181–7191PubMedCrossRefGoogle Scholar
  163. O’nions J, Allday MJ (2004) Deregulation of the Cell Cycle by the Epstein-Barr Virus. In: Vande Woude GF, Klein G (eds) Advances in Cancer Research. Elsevier, New YorkGoogle Scholar
  164. Oudejans JJ, Dukers DF, Jiwa NM, van den Brule AJ, Grasser FA, de Bruin PC, Horstman A, Vos W, van Gorp J, Middeldorp JM, Meijer CJ (1996) Expression of epstein-barr virus encoded nuclear antigen 1 in benign and malignant tissues harbouring EBV. J Clin Pathol 49:897–902PubMedCentralPubMedCrossRefGoogle Scholar
  165. Panagopoulos D, Victoratos P, Alexiou M, Kollias G, Mosialos G (2004) Comparative analysis of signal transduction by CD40 and the Epstein-Barr virus oncoprotein LMP1 in vivo. J Virol 78:13253–13261PubMedCentralPubMedCrossRefGoogle Scholar
  166. Parker GA, Crook T, Bain M, Sara EA, Farrell PJ, Allday MJ (1996) Epstein-Barr virus nuclear antigen (EBNA)3C is an immortalizing oncoprotein with similar properties to adenovirus E1A and papillomavirus E7. Oncogene 13:2541–2549PubMedGoogle Scholar
  167. Pegtel DM, Middeldorp J, Thorley-Lawson DA (2004) Epstein-Barr virus infection in ex vivo tonsil epithelial cell cultures of asymptomatic carriers. J Virol 78:12613–12624PubMedCentralPubMedCrossRefGoogle Scholar
  168. Penn I (1998) The role of immunosuppression in lymphoma formation. Springer Semin Immunopathol 20:343–355PubMedCrossRefGoogle Scholar
  169. Perry ME (1994) The specialised structure of crypt epithelium in the human palatine tonsil and its functional significance. J Anat 185(Pt 1):111–127PubMedCentralPubMedGoogle Scholar
  170. Perry M, Whyte A (1998) Immunology of the tonsils. Immunol Today 19:414–421PubMedCrossRefGoogle Scholar
  171. Polack A, Hortnagel K, Pajic A, Christoph B, Baier B, Falk M, Mautner J, Geltinger C, Bornkamm GW, Kempkes B (1996) c-myc activation renders proliferation of Epstein-Barr virus (EBV)- transformed cells independent of EBV nuclear antigen 2 and latent membrane protein 1. Proc Natl Acad Sci U S A 93:10411–10416PubMedCentralPubMedCrossRefGoogle Scholar
  172. Pope JH, Horne MK, Scott W (1968) Transformation of foetal human keukocytes in vitro by filtrates of a human leukaemic cell line containing herpes-like virus. Int J Cancer 3:857–866PubMedCrossRefGoogle Scholar
  173. Price AM, Luftig MA (2014) Dynamic Epstein-Barr virus gene expression on the path to B-cell transformation. Adv Virus Res 88:279–313PubMedCrossRefGoogle Scholar
  174. Purtilo DT, Cassel CK, Yang JP, Harper R (1975) X-linked recessive progressive combined variable immunodeficiency (Duncan’s disease). Lancet 1:935–940PubMedCrossRefGoogle Scholar
  175. Qu L, Rowe DT (1992) Epstein-Barr virus latent gene expression in uncultured peripheral blood lymphocytes. J Virol 66:3715–3724PubMedCentralPubMedGoogle Scholar
  176. Quigley MF, Gonzalez VD, Granath A, Andersson J, Sandberg JK (2007) CXCR5+ CCR7− CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles. Eur J Immunol 37:3352–3362PubMedCrossRefGoogle Scholar
  177. Raab-Traub N (2002) Epstein-Barr virus in the pathogenesis of NPC. Semin Cancer Biol 12:431–441PubMedCrossRefGoogle Scholar
  178. Raab-Traub N, Dambaugh T, Kieff E (1980) DNA of Epstein-Barr virus VIII: B95-8, the previous prototype, is an unusual deletion derivative. Cell 22:257–267PubMedCrossRefGoogle Scholar
  179. Raab-Traub N, Rajadurai P, Flynn K, Lanier AP (1991) Epstein-Barr virus infection in carcinoma of the salivary gland. J Virol 65:7032–7036PubMedCentralPubMedGoogle Scholar
  180. Radkov SA, Touitou R, Brehm A, Rowe M, West M, Kouzarides T, Allday MJ (1999) Epstein-Barr virus nuclear antigen 3C interacts with histone deacetylase to repress transcription. J Virol 73:5688–5697PubMedCentralPubMedGoogle Scholar
  181. Ramiro AR, Jankovic M, Eisenreich T, Difilippantonio S, Chen-Kiang S, Muramatsu M, Honjo T, Nussenzweig A, Nussenzweig MC (2004) AID is required for c-myc/IgH chromosome translocations in vivo. Cell 118:431–438PubMedCrossRefGoogle Scholar
  182. Renzette N, Somasundaran M, Brewster F, Coderre J, Weiss ER, McManus M, Greenough T, Tabak B, Garber M, Kowalik TF, Luzuriaga K (2014) Epstein-Barr virus latent membrane protein 1 genetic variability in peripheral blood B cells and oropharyngeal fluids. J Virol 88:3744–3755PubMedCentralPubMedCrossRefGoogle Scholar
  183. Ressing ME, Horst D, Griffin BD, Tellam J, Zuo J, Khanna R, Rowe M, Wiertz EJ (2008) Epstein-Barr virus evasion of CD8(+) and CD4(+) T cell immunity via concerted actions of multiple gene products. Semin Cancer Biol 18:397–408PubMedCrossRefGoogle Scholar
  184. Rickinson AB, Finerty S, Epstein MA (1977) Mechanism of the establishment of Epstein-Barr virus genome-containing lymphoid cell lines from infectious mononucleosis patients: studies with phosphonoacetate. Int J Cancer 20:861–868PubMedCrossRefGoogle Scholar
  185. Robbiani DF, Bothmer A, Callen E, Reina-San-martin B, Dorsett Y, Difilippantonio S, Bolland DJ, Chen HT, Corcoran AE, Nussenzweig A, Nussenzweig MC (2008) AID is required for the chromosomal breaks in c-myc that lead to c-myc/IgH translocations. Cell 135:1028–1038PubMedCentralPubMedCrossRefGoogle Scholar
  186. Rooney C, Howe JG, Speck SH, Miller G (1989) Influence of Burkitt’s lymphoma and primary B cells on latent gene expression by the nonimmortalizing P3J-HR-1 strain of Epstein-Barr virus. J Virol 63:1531–1539PubMedCentralPubMedGoogle Scholar
  187. Rooney CM, Smith CA, Ng CY, Loftin S, Li C, Krance RA, Brenner MK, Heslop HE (1995) Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet 345:9–13PubMedCrossRefGoogle Scholar
  188. Roughan JE, Thorley-Lawson DA (2009) The intersection of Epstein-Barr virus with the germinal center. J Virol 83:3968–3976PubMedCentralPubMedCrossRefGoogle Scholar
  189. Roughan JE, Torgbor C, Thorley-Lawson DA (2010) Germinal center B cells latently infected with Epstein-Barr virus proliferate extensively but do not increase in number. J Virol 84:1158–1168PubMedCentralPubMedCrossRefGoogle Scholar
  190. Salamon D, Adori M, Ujvari D, Wu L, Kis LL, Madapura HS, Nagy N, Klein G, Klein E (2012) Latency type-dependent modulation of Epstein-Barr virus-encoded latent membrane protein 1 expression by type I interferons in B cells. J Virol 86:4701–4707PubMedCentralPubMedCrossRefGoogle Scholar
  191. Sayos J, Wu C, Morra M, Wang N, Zhang X, Allen D, van Schaik S, Notarangelo L, Geha R, Roncarolo MG, Oettgen H, de Vries JE, Aversa G, Terhorst C (1998) The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395:462–469PubMedCrossRefGoogle Scholar
  192. Schaefer BC, Strominger JL, Speck SH (1995) 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 92:10565–10569PubMedCentralPubMedCrossRefGoogle Scholar
  193. Schwickert TA, Victora GD, Fooksman DR, Kamphorst AO, Mugnier MR, Gitlin AD, Dustin ML, Nussenzweig MC (2011) A dynamic T cell-limited checkpoint regulates affinity-dependent B cell entry into the germinal center. J Exp Med 208:1243–1252PubMedCentralPubMedCrossRefGoogle Scholar
  194. Seemayer TA, Gross TG, Egeler RM, Pirruccello SJ, Davis JR, Kelly CM, Okano M, Lanyi A, Sumegi J (1995) X-linked lymphoproliferative disease: twenty-five years after the discovery. Pediatr Res 38:471–478PubMedCrossRefGoogle Scholar
  195. Selin LK, Varga SM, Wong IC, Welsh RM (1998) Protective heterologous antiviral immunity and enhanced immunopathogenesis mediated by memory T cell populations. J Exp Med 188:1705–1715PubMedCentralPubMedCrossRefGoogle Scholar
  196. Shibata D, Weiss LM (1992) Epstein-Barr virus-associated gastric adenocarcinoma. Am J Pathol 140:769–774PubMedCentralPubMedGoogle Scholar
  197. Shibata D, Tokunaga M, Uemura Y, Sato E, Tanaka S, Weiss LM (1991) Association of Epstein-Barr virus with undifferentiated gastric carcinomas with intense lymphoid infiltration. Lymphoepithelioma-like carcinoma. Am J Pathol 139:469–474PubMedCentralPubMedGoogle Scholar
  198. Siemer D, Kurth J, Lang S, Lehnerdt G, Stanelle J, Kuppers R (2008) EBV transformation overrides gene expression patterns of B cell differentiation stages. Mol Immunol 45:3133–3141PubMedCrossRefGoogle Scholar
  199. Sinclair AJ, Farrell PJ (1995) Host cell requirements for efficient infection of quiescent primary B lymphocytes by Epstein-Barr virus. J Virol 69:5461–5468PubMedCentralPubMedGoogle Scholar
  200. Sinclair AJ, Palmero I, Peters G, Farrell PJ (1994) EBNA-2 and EBNA-LP cooperate to cause G0 to G1 transition during immortalization of resting human B lymphocytes by Epstein-Barr virus. EMBO J 13:3321–3328PubMedCentralPubMedGoogle Scholar
  201. Skalsky RL, Corcoran DL, Gottwein E, Frank CL, Kang D, Hafner M, Nusbaum JD, Feederle R, Delecluse HJ, Luftig MA, Tuschl T, Ohler U, Cullen BR (2012) The viral and cellular microRNA targetome in lymphoblastoid cell lines. PLoS Pathog 8:e1002484PubMedCentralPubMedCrossRefGoogle Scholar
  202. Souza TA, Stollar BD, Sullivan JL, Luzuriaga K, Thorley-Lawson DA (2005) Peripheral B cells latently infected with Epstein-Barr virus display molecular hallmarks of classical antigen-selected memory B cells. Proc Natl Acad Sci USA 102:18093–18098PubMedCentralPubMedCrossRefGoogle Scholar
  203. Souza TA, Stollar BD, Sullivan JL, Luzuriaga K, Thorley-Lawson DA (2007) Influence of EBV on the peripheral blood memory B cell compartment. J Immunol 179:3153–3160PubMedCrossRefGoogle Scholar
  204. Speck SH (2002) EBV framed in Burkitt lymphoma. Nat Med 8:1086–1087PubMedCrossRefGoogle Scholar
  205. Spencer J, Finn T, Pulford KA, Mason DY, Isaacson PG (1985) The human gut contains a novel population of B lymphocytes which resemble marginal zone cells. Clin Exp Immunol 62:607–612PubMedCentralPubMedGoogle Scholar
  206. Spencer J, Perry ME, Dunn-Walters DK (1998) Human marginal-zone B cells. Immunol Today 19:421–426PubMedCrossRefGoogle Scholar
  207. Stadanlick JE, Cancro MP (2008) BAFF and the plasticity of peripheral B cell tolerance. Curr Opin Immunol 20:158–161PubMedCentralPubMedCrossRefGoogle Scholar
  208. Starzl TE, Nalesnik MA, Porter KA, Ho M, Iwatsuki S, Griffith BP, Rosenthal JT, Hakala TR, Jr Shaw BW, Hardesty RL et al (1984) Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1:583–587PubMedCentralPubMedCrossRefGoogle Scholar
  209. Steven NM, Leese AM, Annels NE, Lee SP, Rickinson AB (1996) Epitope focusing in the primary cytotoxic T cell response to Epstein-Barr virus and its relationship to T cell memory. J Exp Med 184:1801–1813PubMedCrossRefGoogle Scholar
  210. Strang G, Rickinson AB (1987) Multiple HLA class I-dependent cytotoxicities constitute the “non-HLA-restricted” response in infectious mononucleosis. Eur J Immunol 17:1007–1013PubMedCrossRefGoogle Scholar
  211. Sugawara Y, Mizugaki Y, Uchida T, Torii T, Imai S, Makuuchi M, Takada K (1999) Detection of Epstein-Barr virus (EBV) in hepatocellular carcinoma tissue: a novel EBV latency characterized by the absence of EBV-encoded small RNA expression. Virology 256:196–202PubMedCrossRefGoogle Scholar
  212. Swanson-Mungerson M, Longnecker R (2007) Epstein-Barr virus latent membrane protein 2A and autoimmunity. Trends Immunol 28:213–218PubMedCrossRefGoogle Scholar
  213. Swanson-Mungerson MA, Caldwell RG, Bultema R, Longnecker R (2005) Epstein-Barr virus LMP2A alters in vivo and in vitro models of B-cell anergy, but not deletion, in response to autoantigen. J Virol 79:7355–7362PubMedCentralPubMedCrossRefGoogle Scholar
  214. Tang X, Hori S, Osamura RY, Tsutsumi Y (1995) Reticular crypt epithelium and intra-epithelial lymphoid cells in the hyperplastic human palatine tonsil: an immunohistochemical analysis. Pathol Int 45:34–44PubMedCrossRefGoogle Scholar
  215. Tao Q, Ho FC, Loke SL, Srivastava G (1995) Epstein-Barr virus is localized in the tumour cells of nasal lymphomas of NK, T or B cell type. Int J Cancer 60:315–320PubMedCrossRefGoogle Scholar
  216. Thomas JA, Hotchin NA, Allday MJ, Amlot P, Rose M, Yacoub M, Crawford DH (1990) Immunohistology of Epstein-Barr virus-associated antigens in B cell disorders from immunocompromised individuals. Transplantation 49:944–953PubMedCrossRefGoogle Scholar
  217. Thorley-Lawson DA (2001) Epstein-Barr virus: exploiting the immune system. Nat Rev Immunol 1:75–82PubMedCrossRefGoogle Scholar
  218. Thorley-Lawson DA (2005) EBV persistence and latent infection in vivo. In: Robertson ES (ed) Epstein-Barr Virus. Caister Academic Press, NorfolkGoogle Scholar
  219. Thorley-Lawson DA, Allday MJ (2008) The curious case of the tumour virus: 50 years of Burkitt’s lymphoma. Nat Rev Microbiol 6:913–924PubMedCrossRefGoogle Scholar
  220. Thorley-Lawson DA, Babcock GJ (1999) A model for persistent infection with Epstein-Barr virus: the stealth virus of human B cells. Life Sci 65:1433–1453PubMedCrossRefGoogle Scholar
  221. Thorley-Lawson DA, Gross A (2004) Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med 350:1328–1337PubMedCrossRefGoogle Scholar
  222. Thorley-Lawson DA, Mann KP (1985) Early events in Epstein-Barr virus infection provide a model for B cell activation. J Exp Med 162:45–59PubMedCrossRefGoogle Scholar
  223. Thorley-Lawson DA, Poodry CA (1982) Identification and isolation of the main component (gp350–gp220) of Epstein-Barr virus responsible for generating neutralizing antibodies in vivo. J Virol 43:730–736PubMedCentralPubMedGoogle Scholar
  224. Thorley-Lawson DA, Strominger JL (1978) Reversible inhibition by phosphonoacetic acid of human B lymphocyte transformation by Epstein-Barr virus. Virology 86:423–431PubMedCrossRefGoogle Scholar
  225. Thorley-Lawson DA, Schooley RT, Bhan AK, Nadler LM (1982) Epstein-Barr virus superinduces a new human B cell differentiation antigen (B-LAST 1) expressed on transformed lymphoblasts. Cell 30:415–425PubMedCrossRefGoogle Scholar
  226. Thorley-Lawson DA, Nadler LM, Bhan AK, Schooley RT (1985) BLAST-2 [EBVCS], an early cell surface marker of human B cell activation, is superinduced by Epstein Barr virus. Journal of Immunology 134:3007–3012Google Scholar
  227. Thorley-Lawson DA, Hawkins JB, Tracy SI, Shapiro M (2013) The pathogenesis of Epstein-Barr virus persistent infection. Curr Opin Virol 3:227–232PubMedCentralPubMedCrossRefGoogle Scholar
  228. Tierney RJ, Steven N, Young LS, Rickinson AB (1994) Epstein-Barr virus latency in blood mononuclear cells: analysis of viral gene transcription during primary infection and in the carrier state. J Virol 68:7374–7385PubMedCentralPubMedGoogle Scholar
  229. Timmons CF, Dawson DB, Richards CS, Andrews WS, Katz JA (1995) Epstein-Barr virus-associated leiomyosarcomas in liver transplantation recipients. Origin from either donor or recipient tissue. Cancer 76:1481–1489PubMedCrossRefGoogle Scholar
  230. Torgbor C, Awuah P, Deitsch K, Kalantari P, Duca KA, Thorley-Lawson DA (2014) A multifactorial role for P. falciparum malaria in endemic Burkitt’s lymphoma pathogenesis. PLoS Pathog 10:e1004170PubMedCentralPubMedCrossRefGoogle Scholar
  231. Touitou R, Hickabottom M, Parker G, Crook T, Allday MJ (2001) Physical and functional interactions between the corepressor CtBP and the Epstein-Barr virus nuclear antigen EBNA3C. J Virol 75:7749–7755PubMedCentralPubMedCrossRefGoogle Scholar
  232. Tracy SI, Kakalacheva K, Lunemann JD, Luzuriaga K, Middeldorp J, Thorley-Lawson DA (2012) Persistence of Epstein-Barr virus in self-reactive memory B cells. J Virol 86:12330–12340PubMedCentralPubMedCrossRefGoogle Scholar
  233. Tsai CN, Liu ST, Chang YS (1995) 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 14:767–776PubMedCrossRefGoogle Scholar
  234. Tugizov SM, Berline JW, Palefsky JM (2003) Epstein-Barr virus infection of polarized tongue and nasopharyngeal epithelial cells. Nat Med 9:307–314PubMedCrossRefGoogle Scholar
  235. Tugizov SM, Herrera R, Palefsky JM (2013) Epstein-Barr virus transcytosis through polarized oral epithelial cells. J Virol 87:8179–8194PubMedCentralPubMedCrossRefGoogle Scholar
  236. Uchida J, Yasui T, Takaoka-Shichijo Y, Muraoka M, Kulwichit W, Raab-Traub N, Kikutani H (1999) Mimicry of CD40 signals by Epstein-Barr virus LMP1 in B lymphocyte responses. Science 286:300–303PubMedCrossRefGoogle Scholar
  237. van Gelder T, Vuzevski VD, Weimar W (1995) Epstein-Barr virus in smooth-muscle tumors. N Engl J Med 332:1719PubMedCrossRefGoogle Scholar
  238. Vereide D, Sugden B (2009) Proof for EBV’s sustaining role in Burkitt’s lymphomas. Semin Cancer Biol 19:389–393PubMedCentralPubMedCrossRefGoogle Scholar
  239. Vereide DT, Seto E, Chiu YF, Hayes M, Tagawa T, Grundhoff A, Hammerschmidt W, Sugden B (2014) Epstein-Barr virus maintains lymphomas via its miRNAs. Oncogene 33:1258–1264PubMedCentralPubMedCrossRefGoogle Scholar
  240. Victora GD, Nussenzweig MC (2012) Germinal centers. Annu Rev Immunol 30:429–457PubMedCrossRefGoogle Scholar
  241. Victora GD, Schwickert TA, Fooksman DR, Kamphorst AO, Meyer-Hermann M, Dustin ML, Nussenzweig MC (2010) Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143:592–605PubMedCentralPubMedCrossRefGoogle Scholar
  242. Victora GD, Dominguez-Sola D, Holmes AB, Deroubaix S, Dalla-Favera R, Nussenzweig MC (2012) Identification of human germinal center light and dark zone cells and their relationship to human B-cell lymphomas. Blood 120:2240–2248PubMedCentralPubMedCrossRefGoogle Scholar
  243. Vrazo AC, Chauchard M, Raab-Traub N, Longnecker R (2012) Epstein-Barr virus LMP2A reduces hyperactivation induced by LMP1 to restore normal B cell phenotype in transgenic mice. PLoS Pathog 8:e1002662PubMedCentralPubMedCrossRefGoogle Scholar
  244. Wade M, Allday MJ (2000) Epstein-Barr virus suppresses a G(2)/M checkpoint activated by genotoxins. Mol Cell Biol 20:1344–1360PubMedCentralPubMedCrossRefGoogle Scholar
  245. Wang F (2013) Nonhuman primate models for Epstein-Barr virus infection. Curr Opin Virol 3:233–237PubMedCentralPubMedCrossRefGoogle Scholar
  246. Wang D, Liebowitz D, Kieff E (1985) An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell 43:831–840PubMedCrossRefGoogle Scholar
  247. Weill JC, Weller S, Reynaud CA (2009) Human marginal zone B cells. Annu Rev Immunol 27:267–285PubMedCrossRefGoogle Scholar
  248. Weller S, Braun MC, Tan BK, Rosenwald A, Cordier C, Conley ME, Plebani A, Kumararatne DS, Bonnet D, Tournilhac O, Tchernia G, Steiniger B, Staudt LM, Casanova JL, Reynaud CA, Weill JC (2004) Human blood IgM “memory” B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire. Blood 104:3647–3654PubMedCentralPubMedCrossRefGoogle Scholar
  249. White RE, Groves IJ, Turro E, Yee J, Kremmer E, Allday MJ (2010) Extensive co-operation between the Epstein-Barr virus EBNA3 proteins in the manipulation of host gene expression and epigenetic chromatin modification. PLoS ONE 5:e13979PubMedCentralPubMedCrossRefGoogle Scholar
  250. White RE, Ramer PC, Naresh KN, Meixlsperger S, Pinaud L, Rooney C, Savoldo B, Coutinho R, Bodor C, Gribben J, Ibrahim HA, Bower M, Nourse JP, Gandhi MK, Middeldorp J, Cader FZ, Murray P, Munz C, Allday MJ (2012) EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors. J Clin Invest 122:1487–1502PubMedCentralPubMedCrossRefGoogle Scholar
  251. Wilson JB, Bell JL, Levine AJ (1996) Expression of Epstein-Barr virus nuclear antigen-1 induces B cell neoplasia in transgenic mice. EMBO J 15:3117–3126PubMedCentralPubMedGoogle Scholar
  252. Woisetschlaeger M, Yandava CN, Furmanski LA, Strominger JL, Speck SH (1990) Promoter switching in Epstein-Barr virus during the initial stages of infection of B lymphocytes. Proc Natl Acad Sci USA 87:1725–1729PubMedCentralPubMedCrossRefGoogle Scholar
  253. Wood TA, Frenkel EP (1967) The atypical lymphocyte. Am J Med 42:923–936PubMedCrossRefGoogle Scholar
  254. Xu W, He B, Chiu A, Chadburn A, Shan M, Buldys M, Ding A, Knowles DM, Santini PA, Cerutti A (2007) Epithelial cells trigger frontline immunoglobulin class switching through a pathway regulated by the inhibitor SLPI. Nat Immunol 8:294–303PubMedCrossRefGoogle Scholar
  255. Yao QY, Rickinson AB, Epstein MA (1985) A re-examination of the Epstein-Barr virus carrier state in healthy seropositive individuals. Int J Cancer 35:35–42PubMedCrossRefGoogle Scholar
  256. Yates JL, Warren N, Sugden B (1985) Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells. Nature 313:812–815PubMedCrossRefGoogle Scholar
  257. Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N, de Waard R, Leung C, Nouri-Shirazi M, Orazi A, Chaganti RS, Rothman P, Stall AM, Pandolfi PP, Dalla-Favera R (1997) The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat Genet 16:161–170PubMedCrossRefGoogle Scholar
  258. Youinou P, Jamin C, Lydyard PM (1999) CD5 expression in human B-cell populations. Immunol Today 20:312–316PubMedCrossRefGoogle Scholar
  259. Zimber-Strobl U, Strobl LJ (2001) EBNA2 and Notch signalling in Epstein-Barr virus mediated immortalization of B lymphocytes. Semin Cancer Biol 11:423–434PubMedCrossRefGoogle Scholar

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© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.School of MedicineTufts UniversityBostonUSA

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