Epstein-Barr virus (EBV) is usually acquired silently early in life and carried thereafter as an asymptomatic infection of the B lymphoid system. However, many circumstances disturb the delicate EBV-host balance and cause the virus to display its pathogenic potential. Thus, primary infection in adolescence can manifest as infectious mononucleosis (IM), as a fatal illness that magnifies the immunopathology of IM in boys with the X-linked lymphoproliferative disease trait, and as a chronic active disease leading to life-threatening hemophagocytosis in rare cases of T or natural killer (NK) cell infection. Patients with primary immunodeficiencies affecting the NK and/or T cell systems, as well as immunosuppressed transplant recipients, handle EBV infections poorly, and many are at increased risk of virus-driven B-lymphoproliferative disease. By contrast, a range of other EBV-positive malignancies of lymphoid or epithelial origin arise in individuals with seemingly intact immune systems through mechanisms that remain to be understood.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Longnecker L, Kieff E, Cohen JI. 1.  2013. Epstein-Barr virus. Fields Virology DM Knipe, PM Howley, JI Cohen, DE Griffith, RA Lamb, MA Martin, V Racaniello, B Roizman 1898–959 Philadelphia: Lippincott Williams & Wilkins [Google Scholar]
  2. Ascherio A, Munger KL. 2.  2010. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: Epstein-Barr virus and multiple sclerosis: epidemiological evidence. Clin. Exp. Immunol. 160120–24 [Google Scholar]
  3. Rickinson AB. 3.  2014. Co-infections, inflammation and oncogenesis: future directions for EBV research. Semin. Cancer Biol. 26:99–115 [Google Scholar]
  4. Wang F. 4.  2013. Nonhuman primate models for Epstein-Barr virus infection. Curr. Opin. Virol. 3:233–37 [Google Scholar]
  5. Chatterjee B, Leung CS, Münz C. 5.  2014. Animal models of Epstein Barr virus infection. J. Immunol. Methods 410:80–87 [Google Scholar]
  6. Thorley-Lawson DA, Hawkins JB, Tracy SI, Shapiro M. 6.  2013. The pathogenesis of Epstein-Barr virus persistent infection. Curr. Opin. Virol. 3:227–32 [Google Scholar]
  7. Kelly GL, Long HM, Stylianou J, Thomas WA, Leese A. 7.  et al. 2009. An Epstein-Barr virus anti-apoptotic protein constitutively expressed in transformed cells and implicated in Burkitt lymphomagenesis: the Wp/BHRF1 link. PLOS Pathog. 5:e1000341 [Google Scholar]
  8. Jochum S, Moosmann A, Lang S, Hammerschmidt W, Zeidler R. 8.  2012. The EBV immunoevasins vIL-10 and BNLF2a protect newly infected B cells from immune recognition and elimination. PLOS Pathog. 8:e1002704 [Google Scholar]
  9. Abbott RJ, Quinn LL, Leese AM, Scholes HM, Pachnio A, Rickinson AB. 9.  2013. CD8+ T cell responses to lytic EBV infection: late antigen specificities as subdominant components of the total response. J. Immunol. 191:5398–409 [Google Scholar]
  10. Luzuriaga K, Sullivan JL. 10.  2010. Infectious mononucleosis. N. Engl. J. Med. 362:1993–2000 [Google Scholar]
  11. Balfour HH Jr, Odumade OA, Schmeling DO, Mullan BD, Ed JA. 11.  et al. 2013. Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein-Barr virus infection in university students. J. Infect. Dis. 207:80–88 [Google Scholar]
  12. Hoshino Y, Nishikawa K, Ito Y, Kuzushima K, Kimura H. 12.  2011. Kinetics of Epstein-Barr virus load and virus-specific CD8+ T cells in acute infectious mononucleosis. J. Clin. Virol. 50:244–46 [Google Scholar]
  13. Azzi T, Lünemann A, Murer A, Ueda S, Béziat V. 13.  et al. 2014. Role for early-differentiated natural killer cells in infectious mononucleosis. Blood 124:2533–43 [Google Scholar]
  14. Williams H, McAulay K, Macsween KF, Gallacher NJ, Higgins CD. 14.  et al. 2005. The immune response to primary EBV infection: a role for natural killer cells. Br. J. Haematol. 129:266–74 [Google Scholar]
  15. Zhang Y, Wallace DL, de Lara CM, Ghattas H, Asquith B. 15.  et al. 2007. In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection. Immunology 121:258–65 [Google Scholar]
  16. Chijioke O, Müller A, Feederle R, Barros MHM, Krieg C. 16.  et al. 2013. Human natural killer cells prevent infectious mononucleosis features by targeting lytic Epstein-Barr virus infection. Cell Rep. 5:1489–98 [Google Scholar]
  17. Strowig T, Brilot F, Arrey F, Bougras G, Thomas D. 17.  et al. 2008. Tonsilar NK cells restrict B cell transformation by the Epstein-Barr virus via IFN-γ. PLOS Pathog. 4:e27 [Google Scholar]
  18. Lünemann A, Vanoaica LD, Azzi T, Nadal D, Münz C. 18.  2013. A distinct subpopulation of human NK cells restricts B cell transformation by EBV. J. Immunol. 191:4989–95 [Google Scholar]
  19. Gaudreault E, Fiola S, Olivier M, Gosselin J. 19.  2007. Epstein-Barr virus induces MCP-1 secretion by human monocytes via TLR2. J. Virol. 81:8016–24 [Google Scholar]
  20. Fiola S, Gosselin D, Takada K, Gosselin J. 20.  2010. TLR9 contributes to the recognition of EBV by primary monocytes and plasmacytoid dendritic cells. J. Immunol. 185:3620–31 [Google Scholar]
  21. Quan TE, Roman RM, Rudenga BJ, Holers VM, Craft JE. 21.  2010. Epstein-Barr virus promotes interferon-α production by plasmacytoid dendritic cells. Arthritis Rheum. 62:1693–701 [Google Scholar]
  22. Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van Eijndhoven MA, Hopmans ES. 22.  et al. 2010. Functional delivery of viral miRNAs via exosomes. PNAS 107:6328–33 [Google Scholar]
  23. Iwakiri D, Zhou L, Samanta M, Matsumoto M, Ebihara T. 23.  et al. 2009. Epstein-Barr virus (EBV)-encoded small RNA is released from EBV-infected cells and activates signaling from Toll-like receptor 3. J. Exp. Med. 206:2091–99 [Google Scholar]
  24. van Gent M, Braem SG, de Jong A, Delagic N, Peeters JG. 24.  et al. 2014. Epstein-Barr virus large tegument protein BPLF1 contributes to innate immune evasion through interference with Toll-like receptor signaling. PLOS Pathog. 10:e1003960 [Google Scholar]
  25. Iskra S, Kalla M, Delecluse HJ, Hammerschmidt W, Moosmann A. 25.  2010. Toll-like receptor agonists synergistically increase proliferation and activation of B cells by Epstein-Barr virus. J. Virol. 84:3612–23 [Google Scholar]
  26. Hoebe EK, Le Large TYS, Greijer AE, Middeldorp JM. 26.  2013. BamHI-A rightward frame 1, an Epstein–Barr virus-encoded oncogene and immune modulator. Rev. Med. Virol. 23:367–83 [Google Scholar]
  27. Ohashi M, Fogg MH, Orlova N, Quink C, Wang F. 27.  2012. An Epstein-Barr virus encoded inhibitor of Colony Stimulating Factor-1 signaling is an important determinant for acute and persistent EBV infection. PLOS Pathog. 8:e1003095 [Google Scholar]
  28. Guerrero-Ramos A, Patel M, Kadakia K, Haque T. 28.  2014. Performance of the architect EBV antibody panel for determination of Epstein-Barr virus infection stage in immunocompetent adolescents and young adults with clinical suspicion of infectious mononucleosis. Clin. Vaccine Immunol. 21:817–23 [Google Scholar]
  29. Henle W, Henle G, Andersson J, Ernberg I, Klein G. 29.  et al. 1987. Antibody responses to Epstein-Barr virus-determined nuclear antigen (EBNA)-1 and EBNA-2 in acute and chronic Epstein-Barr virus infection. PNAS 84:570–74 [Google Scholar]
  30. Hislop AD, Taylor GS, Sauce D, Rickinson AB. 30.  2007. Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu. Rev. Immunol. 25:587–617 [Google Scholar]
  31. Rowe M, Zuo J. 31.  2010. Immune responses to Epstein-Barr virus: molecular interactions in the virus evasion of CD8+ T cell immunity. Microbes Infect. 12:173–81 [Google Scholar]
  32. Quinn LL, Zuo J, Abbott RJ, Shannon-Lowe C, Tierney RJ. 32.  et al. 2014. Cooperation between Epstein-Barr virus immune evasion proteins spreads protection from CD8+ T cell recognition across all three phases of the lytic cycle. PLOS Pathog. 10:e1004322 [Google Scholar]
  33. Rickinson AB, Long HM, Palendira U, Münz C, Hislop AD. 33.  2014. Cellular immune controls over Epstein–Barr virus infection: new lessons from the clinic and the laboratory. Trends Immunol. 35:159–69 [Google Scholar]
  34. Hislop AD, Kuo M, Drake-Lee AB, Akbar AN, Bergler W. 34.  et al. 2005. Tonsillar homing of Epstein-Barr virus-specific CD8+ T cells and the virus-host balance. J. Clin. Investig. 115:2546–55 [Google Scholar]
  35. Apcher S, Komarova A, Daskalogianni C, Yin Y, Malbert-Colas L, Fahraeus R. 35.  2009. mRNA translation regulation by the Gly-Ala repeat of Epstein-Barr virus nuclear antigen 1. J. Virol. 83:1289–98 [Google Scholar]
  36. Apcher S, Daskalogianni C, Manoury B, Fahraeus R. 36.  2010. Epstein Barr virus-encoded EBNA1 interference with MHC class I antigen presentation reveals a close correlation between mRNA translation initiation and antigen presentation. PLOS Pathog. 6e1001151 [Google Scholar]
  37. Tellam JT, Lekieffre L, Zhong J, Lynn DJ, Khanna R. 37.  2012. Messenger RNA sequence rather than protein sequence determines the level of self-synthesis and antigen presentation of the EBV-encoded antigen, EBNA1. PLOS Pathog. 8:e1003112 [Google Scholar]
  38. Murat P, Zhong J, Lekieffre L, Cowieson NP, Clancy JL. 38.  et al. 2014. G-quadruplexes regulate Epstein-Barr virus–encoded nuclear antigen 1 mRNA translation. Nat. Chem. Biol. 10:358–64 [Google Scholar]
  39. Blake N, Haigh T, Shaka'a G, Croom-Carter D, Rickinson A. 39.  2000. The importance of exogenous antigen in priming the human CD8+ T cell response: lessons from the EBV nuclear antigen EBNA1. J. Immunol. 165:7078–87 [Google Scholar]
  40. Callan MF, Fazou C, Yang H, Rostron T, Poon K. 40.  et al. 2000. CD8+ T-cell selection, function, and death in the primary immune response in vivo. J. Clin. Investig. 106:1251–61 [Google Scholar]
  41. Hadinoto V, Shapiro M, Greenough TC, Sullivan JL, Luzuriaga K, Thorley-Lawson DA. 41.  2008. On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis. Blood 111:1420–27 [Google Scholar]
  42. Balfour HH Jr, Holman CJ, Hokanson KM, Lelonek MM, Giesbrecht JE. 42.  et al. 2005. A prospective clinical study of Epstein-Barr virus and host interactions during acute infectious mononucleosis. J. Infect. Dis. 192:1505–12 [Google Scholar]
  43. Fafi-Kremer S, Morand P, Brion JP, Pavese P, Baccard M. 43.  et al. 2005. Long-term shedding of infectious Epstein-Barr virus after infectious mononucleosis. J. Infect. Dis. 191:985–89 [Google Scholar]
  44. Catalina MD, Sullivan JL, Bak KR, Luzuriaga K. 44.  2001. Differential evolution and stability of epitope-specific CD8+ T cell responses in EBV infection. J. Immunol. 167:4450–57 [Google Scholar]
  45. Woodberry T, Suscovich TJ, Henry LM, Davis JK, Frahm N. 45.  et al. 2005. Differential targeting and shifts in the immunodominance of Epstein-Barr virus–specific CD8 and CD4 T cell responses during acute and persistent infection. J. Infect. Dis. 192:1513–24 [Google Scholar]
  46. Hislop AD, Annels NE, Gudgeon NH, Leese AM, Rickinson AB. 46.  2002. Epitope-specific evolution of human CD8+ T cell responses from primary to persistent phases of Epstein-Barr virus infection. J. Exp. Med. 195:893–905 [Google Scholar]
  47. Odumade OA, Knight JA, Schmeling DO, Masopust D, Balfour HH Jr, Hogquist KA. 47.  2012. Primary Epstein-Barr virus infection does not erode preexisting CD8+ T cell memory in humans. J. Exp. Med. 209:471–78 [Google Scholar]
  48. Lelic A, Verschoor CP, Ventresca M, Parsons R, Evelegh C. 48.  et al. 2012. The polyfunctionality of human memory CD8+ T cells elicited by acute and chronic virus infections is not influenced by age. PLOS Pathog. 8:e1003076 [Google Scholar]
  49. Klarenbeek PL, Remmerswaal EB, ten Berge IJ, Doorenspleet ME, van Schaik BD. 49.  et al. 2012. Deep sequencing of antiviral T-cell responses to HCMV and EBV in humans reveals a stable repertoire that is maintained for many years. PLOS Pathog. 8:e1002889 [Google Scholar]
  50. Iancu EM, Gannon PO, Laurent J, Gupta B, Romero P. 50.  et al. 2013. Persistence of EBV antigen-specific CD8 T cell clonotypes during homeostatic immune reconstitution in cancer patients. PLOS ONE 8:e78686 [Google Scholar]
  51. Sulik A, Oldak E, Kroten A, Lipska A, Radziwon P. 51.  2014. Epstein-Barr virus effect on frequency of functionally distinct T cell subsets in children with infectious mononucleosis. Adv. Med. Sci. 59:227–31 [Google Scholar]
  52. Amyes E, Hatton C, Montamat-Sicotte D, Gudgeon N, Rickinson AB. 52.  et al. 2003. Characterization of the CD4+ T cell response to Epstein-Barr virus during primary and persistent infection. J. Exp. Med. 198:903–11 [Google Scholar]
  53. Precopio ML, Sullivan JL, Willard C, Somasundaran M, Luzuriaga K. 53.  2003. Differential kinetics and specificity of EBV-specific CD4+ and CD8+ T cells during primary infection. J. Immunol. 170:2590–98 [Google Scholar]
  54. Long HM, Chagoury OL, Leese AM, Ryan GB, James E. 54.  et al. 2013. MHC II tetramers visualize human CD4+ T cell responses to Epstein-Barr virus infection and demonstrate atypical kinetics of the nuclear antigen EBNA1 response. J. Exp. Med. 210:933–49 [Google Scholar]
  55. Miyawaki T, Kasahara Y, Kanegane H, Ohta K, Yokoi T. 55.  et al. 1991. Expression of CD45R0 (UCHL1) by CD4+ and CD8+ T cells as a sign of in vivo activation in infectious mononucleosis. Clin. Exp. Immunol. 83:447–51 [Google Scholar]
  56. Long HM, Leese AM, Chagoury OL, Connerty SR, Quarcoopome J. 56.  et al. 2011. Cytotoxic CD4+ T cell responses to EBV contrast with CD8 responses in breadth of lytic cycle antigen choice and in lytic cycle recognition. J. Immunol. 187:92–101 [Google Scholar]
  57. Mautner J, Bornkamm GW. 57.  2012. The role of virus-specific CD4+ T cells in the control of Epstein-Barr virus infection. Eur. J. Cell Biol. 91:31–35 [Google Scholar]
  58. Ning RJ, Xu XQ, Chan KH, Chiang AK. 58.  2011. Long-term carriers generate Epstein–Barr virus (EBV)-specific CD4+ and CD8+ polyfunctional T-cell responses which show immunodominance hierarchies of EBV proteins. Immunology 134:161–71 [Google Scholar]
  59. Leung CS, Maurer MA, Meixlsperger S, Lippmann A, Cheong C. 59.  et al. 2013. Robust T-cell stimulation by Epstein-Barr virus-transformed B cells after antigen targeting to DEC-205. Blood 121:1584–94 [Google Scholar]
  60. Münz C, Bickham KL, Subklewe M, Tsang ML, Chahroudi A. 60.  et al. 2000. Human CD4+ T lymphocytes consistently respond to the latent Epstein-Barr virus nuclear antigen EBNA1. J. Exp. Med. 191:1649–60 [Google Scholar]
  61. Leen A, Meij P, Redchenko I, Middeldorp J, Bloemena E. 61.  et al. 2001. Differential immunogenicity of Epstein-Barr virus latent-cycle proteins for human CD4+ T-helper 1 responses. J. Virol. 75:8649–59 [Google Scholar]
  62. Scherrenburg J, Piriou E, Nanlohy NM, van Baarle D. 62.  2008. Detailed analysis of Epstein–Barr virus-specific CD4+ and CD8+ T cell responses during infectious mononucleosis. Clin. Exp. Immunol. 153:231–39 [Google Scholar]
  63. Taylor GS, Long HM, Haigh TA, Larsen M, Brooks J, Rickinson AB. 63.  2006. A role for intercellular antigen transfer in the recognition of EBV-transformed B cell lines by EBV nuclear antigen-specific CD4+ T cells. J. Immunol. 177:3746–56 [Google Scholar]
  64. Leung CS, Haigh TA, Mackay LK, Rickinson AB, Taylor GS. 64.  2010. Nuclear location of an endogenously expressed antigen, EBNA1, restricts access to macroautophagy and the range of CD4 epitope display. PNAS 107:2165–70 [Google Scholar]
  65. Paludan C, Schmid D, Landthaler M, Vockerodt M, Kube D. 65.  et al. 2005. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307:593–96 [Google Scholar]
  66. Wingate PJ, McAulay KA, Anthony IC, Crawford DH. 66.  2009. Regulatory T cell activity in primary and persistent Epstein-Barr virus infection. J. Med. Virol. 81:870–77 [Google Scholar]
  67. Cárdenas Sierra D, Vélez Colmenares G, Orfao de Matos A, Fiorentino Gómez S, Quijano Gómez SM. 67.  2014. Age-associated Epstein–Barr virus-specific T cell responses in seropositive healthy adults. Clin. Exp. Immunol. 177:320–32 [Google Scholar]
  68. Nikiforow S, Bottomly K, Miller G, Münz C. 68.  2003. Cytolytic CD4+-T-cell clones reactive to EBNA1 inhibit Epstein-Barr virus-induced B-cell proliferation. J. Virol. 77:12088–104 [Google Scholar]
  69. Khanna R, Burrows SR, Thomson SA, Moss DJ, Cresswell P. 69.  et al. 1997. Class I processing-defective Burkitt's lymphoma cells are recognized efficiently by CD4+ EBV-specific CTLs. J. Immunol. 158:3619–25 [Google Scholar]
  70. Zuo J, Rowe M. 70.  2012. Herpesviruses placating the unwilling host: manipulation of the MHC class II antigen presentation pathway. Viruses 4:1335–53 [Google Scholar]
  71. Rostgaard K, Wohlfahrt J, Hjalgrim H. 71.  2014. A genetic basis for infectious mononucleosis: evidence from a family study of hospitalized cases in Denmark. Clin. Infect. Dis. 58:1684–89 [Google Scholar]
  72. Hwang AE, Hamilton AS, Cockburn MG, Ambinder R, Zadnick J. 72.  et al. 2012. Evidence of genetic susceptibility to infectious mononucleosis: a twin study. Epidemiol. Infect. 140:2089–95 [Google Scholar]
  73. Helminen M, Lahdenpohja N, Hurme M. 73.  1999. Polymorphism of the interleukin-10 gene is associated with susceptibility to Epstein-Barr virus infection. J. Infect. Dis. 180:496–99 [Google Scholar]
  74. Vollmer-Conna U, Piraino BF, Cameron B, Davenport T, Hickie I. 74.  et al. 2008. Cytokine polymorphisms have a synergistic effect on severity of the acute sickness response to infection. Clin. Infect. Dis. 47:1418–25 [Google Scholar]
  75. Hatta K, Morimoto A, Ishii E, Kimura H, Ueda I. 75.  et al. 2007. Association of transforming growth factor-β1 gene polymorphism in the development of Epstein-Barr virus-related hematologic diseases. Haematologica 92:1470–74 [Google Scholar]
  76. Clute SC, Watkin LB, Cornberg M, Naumov YN, Sullivan JL. 76.  et al. 2005. Cross-reactive influenza virus–specific CD8+ T cells contribute to lymphoproliferation in Epstein-Barr virus–associated infectious mononucleosis. J. Clin. Investig. 115:3602–12 [Google Scholar]
  77. Biggar RJ, Henle G, Bocker J, Lennette ET, Fleisher G, Henle W. 77.  1978. Primary Epstein-Barr virus infections in African infants. II. Clinical and serological observations during seroconversion. Int. J. Cancer 22:244–50 [Google Scholar]
  78. Silins SL, Sherritt MA, Silleri JM, Cross SM, Elliott SL. 78.  et al. 2001. Asymptomatic primary Epstein-Barr virus infection occurs in the absence of blood T-cell repertoire perturbations despite high levels of systemic viral load. Blood 98:3739–44 [Google Scholar]
  79. Imashuku S. 79.  2002. Clinical features and treatment strategies of Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis. Crit. Rev. Oncol. Hematol. 44:259–72 [Google Scholar]
  80. Kimura H, Ito Y, Kawabe S, Gotoh K, Takahashi Y. 80.  et al. 2012. EBV-associated T/NK-cell lymphoproliferative diseases in nonimmunocompromised hosts: prospective analysis of 108 cases. Blood 119:673–86 [Google Scholar]
  81. Fox CP, Shannon-Lowe C, Rowe M. 81.  2011. Deciphering the role of Epstein-Barr virus in the pathogenesis of T and NK cell lymphoproliferations. Herpesviridae 2:8 [Google Scholar]
  82. Sugaya N, Kimura H, Hara S, Hoshino Y, Kojima S. 82.  et al. 2004. Quantitative analysis of Epstein-Barr virus (EBV)-specific CD8+ T cells in patients with chronic active EBV infection. J. Infect. Dis. 190:985–88 [Google Scholar]
  83. Pakpoor J, Disanto G, Gerber JE, Dobson R, Meier UC. 83.  et al. 2013. The risk of developing multiple sclerosis in individuals seronegative for Epstein-Barr virus: a meta-analysis. Mult. Scler. 19:162–66 [Google Scholar]
  84. Pohl D, Krone B, Rostasy K, Kahler E, Brunner E. 84.  et al. 2006. High seroprevalence of Epstein-Barr virus in children with multiple sclerosis. Neurology 67:2063–65 [Google Scholar]
  85. Munger KL, Levin LI, O'Reilly EJ, Falk KI, Ascherio A. 85.  2011. Anti-Epstein-Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel. Mult. Scler. 17:1185–93 [Google Scholar]
  86. Thacker EL, Mirzaei F, Ascherio A. 86.  2006. Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Ann. Neurol. 59:499–503 [Google Scholar]
  87. Lang HL, Jacobsen H, Ikemizu S, Andersson C, Harlos K. 87.  et al. 2002. A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat. Immunol. 3:940–43 [Google Scholar]
  88. Lünemann JD, Edwards N, Muraro PA, Hayashi S, Cohen JI. 88.  et al. 2006. Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. Brain 129:1493–506 [Google Scholar]
  89. Lünemann JD, Jelčić I, Roberts S, Lutterotti A, Tackenberg B. 89.  et al. 2008. EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-γ and IL-2. J. Exp. Med. 205:1763–73 [Google Scholar]
  90. Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R. 90.  et al. 2007. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J. Exp. Med. 204:2899–912 [Google Scholar]
  91. Tzartos JS, Khan G, Vossenkamper A, Cruz-Sadaba M, Lonardi S. 91.  et al. 2012. Association of innate immune activation with latent Epstein-Barr virus in active MS lesions. Neurology 78:15–23 [Google Scholar]
  92. Lassmann H, Niedobitek G, Aloisi F, Middeldorp JM. 92.  2011. Epstein-Barr virus in the multiple sclerosis brain: a controversial issue—report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. Brain 134:2772–86 [Google Scholar]
  93. Pender MP, Csurhes PA, Lenarczyk A, Pfluger CMM, Burrows SR. 93.  2009. Decreased T cell reactivity to Epstein–Barr virus infected lymphoblastoid cell lines in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 80:498–505 [Google Scholar]
  94. Lindsey JW, Hatfield LM. 94.  2010. Epstein-Barr virus and multiple sclerosis: cellular immune response and cross-reactivity. J. Neuroimmunol. 229:238–42 [Google Scholar]
  95. Jilek S, Schluep M, Meylan P, Vingerhoets F, Guignard L. 95.  et al. 2008. Strong EBV-specific CD8+ T-cell response in patients with early multiple sclerosis. Brain 131:1712–21 [Google Scholar]
  96. Jaquiery E, Jilek S, Schluep M, Meylan P, Lysandropoulos A. 96.  et al. 2010. Intrathecal immune responses to EBV in early MS. Eur. J. Immunol. 40:878–87 [Google Scholar]
  97. Tracy SI, Kakalacheva K, Lünemann JD, Luzuriaga K, Middeldorp J, Thorley-Lawson DA. 97.  2012. Persistence of Epstein-Barr virus in self-reactive memory B cells. J. Virol. 86:12330–40 [Google Scholar]
  98. van Sechel AC, Bajramovic JJ, van Stipdonk MJB, Persoon-Deen C, Geutskens SB, van Noort JM. 98.  1999. EBV-induced expression and HLA-DR-restricted presentation by human B cells of αB-crystallin, a candidate autoantigen in multiple sclerosis. J. Immunol. 162:129–35 [Google Scholar]
  99. James JA, Robertson JM. 99.  2012. Lupus and Epstein-Barr. Curr. Opin. Rheumatol. 24:383–88 [Google Scholar]
  100. Moon UY, Park SJ, Oh ST, Kim WU, Park SH. 100.  et al. 2004. Patients with systemic lupus erythematosus have abnormally elevated Epstein-Barr virus load in blood. Arthritis Res. Ther. 6:R295–302 [Google Scholar]
  101. Larsen M, Sauce D, Deback C, Arnaud L, Mathian A. 101.  et al. 2011. Exhausted cytotoxic control of Epstein-Barr virus in human lupus. PLOS Pathog. 7:e1002328 [Google Scholar]
  102. James JA, Neas BR, Moser KL, Hall T, Bruner GR. 102.  et al. 2001. Systemic lupus erythematosus in adults is associated with previous Epstein-Barr virus exposure. Arthritis Rheum. 44:1122–26 [Google Scholar]
  103. James JA, Kaufman KM, Farris AD, Taylor-Albert E, Lehman TJ, Harley JB. 103.  1997. An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus. J. Clin. Investig. 100:3019–26 [Google Scholar]
  104. McClain MT, Heinlen LD, Dennis GJ, Roebuck J, Harley JB, James JA. 104.  2005. Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. Nat. Med. 11:85–89 [Google Scholar]
  105. Parvaneh N, Filipovich AH, Borkhardt A. 105.  2013. Primary immunodeficiencies predisposed to Epstein-Barr virus-driven haematological diseases. Br. J. Haematol. 162:573–86 [Google Scholar]
  106. Tangye SG. 106.  2014. XLP: clinical features and molecular etiology due to mutations in SH2D1A encoding SAP. J. Clin. Immunol. 34:772–79 [Google Scholar]
  107. Cannons JL, Tangye SG, Schwartzberg PL. 107.  2011. SLAM family receptors and SAP adaptors in immunity. Annu. Rev. Immunol. 29:665–705 [Google Scholar]
  108. Katz G, Krummey SM, Larsen SE, Stinson JR, Snow AL. 108.  2014. SAP facilitates recruitment and activation of LCK at NTB-A receptors during restimulation-induced cell death. J. Immunol. 192:4202–9 [Google Scholar]
  109. Cannons JL, Wu JZ, Gomez-Rodriguez J, Zhang J, Dong B. 109.  et al. 2010. Biochemical and genetic evidence for a SAP-PKC-θ interaction contributing to IL-4 regulation. J. Immunol. 185:2819–27 [Google Scholar]
  110. Zhao F, Cannons JL, Dutta M, Griffiths GM, Schwartzberg PL. 110.  2012. Positive and negative signaling through SLAM receptors regulate synapse organization and thresholds of cytolysis. Immunity 36:1003–16 [Google Scholar]
  111. Kageyama R, Cannons JL, Zhao F, Yusuf I, Lao C. 111.  et al. 2012. The receptor Ly108 functions as a SAP adaptor-dependent on-off switch for T cell help to B cells and NKT cell development. Immunity 36:986–1002 [Google Scholar]
  112. Dong Z, Davidson D, Perez-Quintero LA, Kurosaki T, Swat W, Veillette A. 112.  2012. The adaptor SAP controls NK cell activation by regulating the enzymes Vav-1 and SHIP-1 and by enhancing conjugates with target cells. Immunity 36:974–85 [Google Scholar]
  113. Parolini S, Bottino C, Falco M, Augugliaro R, Giliani S. 113.  et al. 2000. X-linked lymphoproliferative disease: 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus–infected cells. J. Exp. Med. 192:337–46 [Google Scholar]
  114. Bottino C, Falco M, Parolini S, Marcenaro E, Augugliaro R. 114.  et al. 2001. NTB-A, a novel SH2D1A-associated surface molecule contributing to the inability of natural killer cells to kill Epstein-Barr virus–infected B cells in X-linked lymphoproliferative disease. J. Exp. Med. 194:235–46 [Google Scholar]
  115. Sharifi R, Sinclair JC, Gilmour KC, Arkwright PD, Kinnon C. 115.  et al. 2004. SAP mediates specific cytotoxic T-cell functions in X-linked lymphoproliferative disease. Blood 103:3821–27 [Google Scholar]
  116. Dupré L, Andolfi G, Tangye SG, Clementi R, Locatelli F. 116.  et al. 2005. SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells. Blood 105:4383–89 [Google Scholar]
  117. Ma CS, Hare NJ, Nichols KE, Dupré L, Andolfi G. 117.  et al. 2005. Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells. J. Clin. Investig. 115:1049–59 [Google Scholar]
  118. Hislop AD, Palendira U, Leese AM, Arkwright PD, Rohrlich PS. 118.  et al. 2010. Impaired Epstein-Barr virus–specific CD8+ T-cell function in X-linked lymphoproliferative disease is restricted to SLAM family–positive B-cell targets. Blood 116:3249–57 [Google Scholar]
  119. Palendira U, Low C, Chan A, Hislop AD, Ho E. 119.  et al. 2011. Molecular pathogenesis of EBV susceptibility in XLP as revealed by analysis of female carriers with heterozygous expression of SAP. PLOS Biol. 9:e1001187 [Google Scholar]
  120. Cannons JL, Qi H, Lu KT, Dutta M, Gomez-Rodriguez J. 120.  et al. 2010. Optimal germinal center responses require a multistage T cell:B cell adhesion process involving integrins, SLAM-associated protein, and CD84. Immunity 32:253–65 [Google Scholar]
  121. Palendira U, Low C, Bell AI, Ma CS, Abbott RJ. 121.  et al. 2012. Expansion of somatically reverted memory CD8+ T cells in patients with X-linked lymphoproliferative disease caused by selective pressure from Epstein-Barr virus. J. Exp. Med. 209:913–24 [Google Scholar]
  122. Rigaud S, Fondanèche MC, Lambert N, Pasquier B, Mateo V. 122.  et al. 2006. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 444:110–14 [Google Scholar]
  123. Liston P, Roy N, Tamai K, Lefebvre C, Baird S. 123.  et al. 1996. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature 379:349–53 [Google Scholar]
  124. Deveraux QL, Takahashi R, Salvesen GS, Reed JC. 124.  1997. X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388:300–4 [Google Scholar]
  125. Krieg A, Correa RG, Garrison JB, Le Negrate G, Welsh K. 125.  et al. 2009. XIAP mediates NOD signaling via interaction with RIP2. PNAS 106:14524–29 [Google Scholar]
  126. Damgaard RB, Nachbur U, Yabal M, Wong WW, Fiil BK. 126.  et al. 2012. The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Mol. Cell 46:746–58 [Google Scholar]
  127. Chung BK, Tsai K, Allan LL, Zheng DJ, Nie JC. 127.  et al. 2013. Innate immune control of EBV-infected B cells by invariant natural killer T cells. Blood 122:2600–8 [Google Scholar]
  128. Lopez-Granados E, Stacey M, Kienzler AK, Sierro S, Willberg CB. 128.  et al. 2014. A mutation in X-linked inhibitor of apoptosis (G466X) leads to memory inflation of Epstein–Barr virus-specific T cells. Clin. Exp. Immunol. 178:470–82 [Google Scholar]
  129. Rigaud S, Lopez-Granados E, Sibéril S, Gloire G, Lambert N. 129.  et al. 2011. Human X-linked variable immunodeficiency caused by a hypomorphic mutation in XIAP in association with a rare polymorphism in CD40LG. Blood 118:252–61 [Google Scholar]
  130. Filipovich AH, Zhang K, Snow AL, Marsh RA. 130.  2010. X-linked lymphoproliferative syndromes: brothers or distant cousins. Blood 116:3398–408 [Google Scholar]
  131. Pachlopnik Schmid J, Canioni D, Moshous D, Touzot F, Mahlaoui N. 131.  et al. 2011. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood 117:1522–29 [Google Scholar]
  132. Orange JS. 132.  2013. Natural killer cell deficiency. J. Allergy Clin. Immunol. 132:515–25 [Google Scholar]
  133. de Vries E, Koene HR, Vossen JM, Gratama JW, von dem Borne AEGK. 133.  et al. 1996. Identification of an unusual Fcγ receptor IIIa (CD16) on natural killer cells in a patient with recurrent infections. Blood 88:3022–27 [Google Scholar]
  134. Jawahar S, Moody C, Chan M, Finberg R, Geha R, Chatila T. 134.  1996. Natural killer (NK) cell deficiency associated with an epitope-deficient Fc receptor type IIIA (CD16-II). Clin. Exp. Immunol. 103:408–13 [Google Scholar]
  135. Grier JT, Forbes LR, Monaco-Shawver L, Oshinsky J, Atkinson TP. 135.  et al. 2012. Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity. J. Clin. Investig. 122:3769–80 [Google Scholar]
  136. Eidenschenk C, Dunne J, Jouanguy E, Fourlinnie C, Gineau L. 136.  et al. 2006. A novel primary immunodeficiency with specific natural-killer cell deficiency maps to the centromeric region of chromosome 8. Am. J. Hum. Genet. 78:721–27 [Google Scholar]
  137. Gineau L, Cognet C, Kara N, Lach FP, Dunne J. 137.  et al. 2012. Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency. J. Clin. Investig. 122:821–32 [Google Scholar]
  138. Hughes CR, Guasti L, Meimaridou E, Chuang CH, Schimenti JC. 138.  et al. 2012. MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans. J. Clin. Investig. 122:814–20 [Google Scholar]
  139. Spinner MA, Sanchez LA, Hsu AP, Shaw PA, Zerbe CS. 139.  et al. 2014. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood 123:809–21 [Google Scholar]
  140. Biron CA, Byron KS, Sullivan JL. 140.  1989. Severe herpesvirus infections in an adolescent without natural killer cells. N. Engl. J. Med. 320:1731–35 [Google Scholar]
  141. Mace EM, Hsu AP, Monaco-Shawver L, Makedonas G, Rosen JB. 141.  et al. 2013. Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56bright subset. Blood 121:2669–77 [Google Scholar]
  142. McClain KL, Leach CT, Jenson HB, Joshi VV, Pollock BH. 142.  et al. 1995. Association of Epstein-Barr virus with leiomyosarcomas in children with AIDS. N. Engl. J. Med. 332:12–18 [Google Scholar]
  143. Hussein K, Maecker-Kolhoff B, Donnerstag F, Laenger F, Kreipe H, Jonigk D. 143.  2013. Epstein-Barr virus-associated smooth muscle tumours after transplantation, infection with human immunodeficiency virus and congenital immunodeficiency syndromes. Pathobiology 80:297–301 [Google Scholar]
  144. Shaw RK, Issekutz AC, Fraser R, Schmit P, Morash B. 144.  et al. 2012. Bilateral adrenal EBV-associated smooth muscle tumors in a child with a natural killer cell deficiency. Blood 119:4009–12 [Google Scholar]
  145. Spritz RA. 145.  1998. Genetic defects in Chediak-Higashi syndrome and the beige mouse. J. Clin. Immunol. 18:97–105 [Google Scholar]
  146. Kaplan J, De Domenico I, Ward DM. 146.  2008. Chediak-Higashi syndrome. Curr. Opin. Hematol. 15:22–29 [Google Scholar]
  147. Ogimi C, Tanaka R, Arai T, Kikuchi A, Hanada R, Oh-Ishi T. 147.  2011. Rituximab and cyclosporine therapy for accelerated phase Chediak-Higashi syndrome. Pediatr. Blood Cancer 57:677–80 [Google Scholar]
  148. Greenspan JS, Greenspan D, Lennette ET, Abrams DI, Conant MA. 148.  et al. 1985. Replication of Epstein-Barr virus within the epithelial cells of oral “hairy” leukoplakia, an AIDS-associated lesion. N. Engl. J. Med. 313:1564–71 [Google Scholar]
  149. Li FY, Chaigne-Delalande B, Kanellopoulou C, Davis JC, Matthews HF. 149.  et al. 2011. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature 475:471–76 [Google Scholar]
  150. Chaigne-Delalande B, Li FY, O'Connor GM, Lukacs MJ, Jiang P. 150.  et al. 2013. Mg2+ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D. Science 341:186–91 [Google Scholar]
  151. Li FY, Chaigne-Delalande B, Su H, Uzel G, Matthews H, Lenardo MJ. 151.  2014. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood 123:2148–52 [Google Scholar]
  152. Moshous D, Martin E, Carpentier W, Lim A, Callebaut I. 152.  et al. 2013. Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation. J. Allergy Clin. Immunol. 131:1594–603 [Google Scholar]
  153. Stray-Pedersen A, Jouanguy E, Crequer A, Bertuch AA, Brown BS. 153.  et al. 2014. Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy. J. Clin. Immunol. 34:871–90 [Google Scholar]
  154. Moshous D, Pannetier C, de Chasseval R, le Deist F, Cavazzana-Calvo M. 154.  et al. 2003. Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis. J. Clin. Investig. 111:381–87 [Google Scholar]
  155. Enders A, Fisch P, Schwarz K, Duffner U, Pannicke U. 155.  et al. 2006. A severe form of human combined immunodeficiency due to mutations in DNA ligase IV. J. Immunol. 176:5060–68 [Google Scholar]
  156. Abdollahpour H, Appaswamy G, Kotlarz D, Diestelhorst J, Beier R. 156.  et al. 2012. The phenotype of human STK4 deficiency. Blood 119:3450–57 [Google Scholar]
  157. Nehme NT, Pachlopnik Schmid J, Debeurme F, Andre-Schmutz I, Lim A. 157.  et al. 2012. MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival. Blood 119:3458–68 [Google Scholar]
  158. Huck K, Feyen O, Niehues T, Ruschendorf F, Hubner N. 158.  et al. 2009. Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. J. Clin. Investig. 119:1350–58 [Google Scholar]
  159. Stepensky P, Weintraub M, Yanir A, Revel-Vilk S, Krux F. 159.  et al. 2011. IL-2-inducible T-cell kinase deficiency: clinical presentation and therapeutic approach. Haematologica 96:472–76 [Google Scholar]
  160. Linka RM, Risse SL, Bienemann K, Werner M, Linka Y. 160.  et al. 2012. Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases. Leukemia 26:963–71 [Google Scholar]
  161. Angulo I, Vadas O, Garçon F, Banham-Hall E, Plagnol V. 161.  et al. 2013. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science 342:866–71 [Google Scholar]
  162. Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK. 162.  et al. 2014. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat. Immunol. 15:88–97 [Google Scholar]
  163. van Montfrans JM, Hoepelman AIM, Otto S, van Gijn M, van de Corput L. 163.  et al. 2012. CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia. J. Allergy Clin. Immunol. 129:787–93.e6 [Google Scholar]
  164. Salzer E, Daschkey S, Choo S, Gombert M, Santos-Valente E. 164.  et al. 2013. Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27. Haematologica 98:473–78 [Google Scholar]
  165. Faulkner GC, Burrows SR, Khanna R, Moss DJ, Bird AG, Crawford DH. 165.  1999. X-linked agammaglobulinemia patients are not infected with Epstein-Barr virus: implications for the biology of the virus. J. Virol. 73:1555–64 [Google Scholar]
  166. Vegso G, Hajdu M, Sebestyen A. 166.  2011. Lymphoproliferative disorders after solid organ transplantation—classification, incidence, risk factors, early detection and treatment options. Pathol. Oncol. Res. 17:443–54 [Google Scholar]
  167. Rasche L, Kapp M, Einsele H, Mielke S. 167.  2014. EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoetic SCT. Bone Marrow Transplant. 49:163–67 [Google Scholar]
  168. Nikoobakht M, Beitollahi J, Nikoobakht N, Aloosh M, Sahebjamee M. 168.  et al. 2011. Evaluation of Epstein–Barr virus load in saliva before and after renal transplantation. Transplant. Proc. 43:540–42 [Google Scholar]
  169. Storek J, Geddes M, Khan F, Huard B, Helg C. 169.  et al. 2008. Reconstitution of the immune system after hematopoietic stem cell transplantation in humans. Semin. Immunopathol. 30:425–37 [Google Scholar]
  170. Landgren O, Gilbert ES, Rizzo JD, Socie G, Banks PM. 170.  et al. 2009. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood 113:4992–5001 [Google Scholar]
  171. Styczynski J, Gil L, Tridello G, Ljungman P, Donnelly JP. 171.  et al. 2013. Response to rituximab-based therapy and risk factor analysis in Epstein Barr virus–related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Clin. Infect. Dis. 57:794–802 [Google Scholar]
  172. Bosch M, Dhadda M, Hoegh-Petersen M, Liu Y, Hagel LM. 172.  et al. 2012. Immune reconstitution after anti-thymocyte globulin-conditioned hematopoietic cell transplantation. Cytotherapy 14:1258–75 [Google Scholar]
  173. Auger S, Orsini M, Ceballos P, Fegueux N, Kanouni T. 173.  et al. 2014. Controlled Epstein-Barr virus reactivation after allogeneic transplantation is associated with improved survival. Eur. J. Haematol. 92:421–28 [Google Scholar]
  174. Chakrabarti S, Milligan DW, Pillay D, Mackinnon S, Holder K. 174.  et al. 2003. Reconstitution of the Epstein-Barr virus–specific cytotoxic T-lymphocyte response following T-cell–depleted myeloablative and nonmyeloablative allogeneic stem cell transplantation. Blood 102:839–42 [Google Scholar]
  175. D'Aveni M, Aissi-Rothe L, Venard V, Salmon A, Falenga A. 175.  et al. 2011. The clinical value of concomitant Epstein Barr virus (EBV)-DNA load and specific immune reconstitution monitoring after allogeneic hematopoietic stem cell transplantation. Transpl. Immunol. 24:224–32 [Google Scholar]
  176. Meij P, van Esser JW, Niesters HG, van Baarle D, Miedema F. 176.  et al. 2003. Impaired recovery of Epstein-Barr virus (EBV)-specific CD8+ T lymphocytes after partially T-depleted allogeneic stem cell transplantation may identify patients at very high risk for progressive EBV reactivation and lymphoproliferative disease. Blood 101:4290–97 [Google Scholar]
  177. Opelz G, Dohler B. 177.  2004. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am. J. Transplant. 4:222–30 [Google Scholar]
  178. Wiesmayr S, Webber SA, Macedo C, Popescu I, Smith L. 178.  et al. 2012. Decreased NKp46 and NKG2D and elevated PD-1 are associated with altered NK-cell function in pediatric transplant patients with PTLD. Eur. J. Immunol. 42:541–50 [Google Scholar]
  179. Gotoh K, Ito Y, Ohta R, Iwata S, Nishiyama Y. 179.  et al. 2010. Immunologic and virologic analyses in pediatric liver transplant recipients with chronic high Epstein-Barr virus loads. J. Infect. Dis. 202:461–69 [Google Scholar]
  180. Macedo C, Donnenberg A, Popescu I, Reyes J, Abu-Elmagd K. 180.  et al. 2005. EBV-specific memory CD8+ T cell phenotype and function in stable solid organ transplant patients. Transpl. Immunol. 14:109–16 [Google Scholar]
  181. Sebelin-Wulf K, Nguyen TD, Oertel S, Papp-Vary M, Trappe RU. 181.  et al. 2007. Quantitative analysis of EBV-specific CD4/CD8 T cell numbers, absolute CD4/CD8 T cell numbers and EBV load in solid organ transplant recipients with PLTD. Transpl. Immunol. 17:203–10 [Google Scholar]
  182. Smets F, Latinne D, Bazin H, Reding R, Otte JB. 182.  et al. 2002. Ratio between Epstein-Barr viral load and anti-Epstein-Barr virus specific T-cell response as a predictive marker of posttransplant lymphoproliferative disease. Transplantation 73:1603–10 [Google Scholar]
  183. Lee TC, Goss JA, Rooney CM, Heslop HE, Barshes NR. 183.  et al. 2006. Quantification of a low cellular immune response to aid in identification of pediatric liver transplant recipients at high-risk for EBV infection. Clin. Transplant. 20:689–94 [Google Scholar]
  184. Swerdlow SH, Webber SA, Chadburn A, Ferry JA. 184.  2008. Post-transplant lymphoproliferative disorders. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues SJ Swerdlow, E Campo, NL Harris, ES Jaffe, SA Pileri, H Stein, J Thiele, JW Vardiman 343–49 Lyon, Fr.: IARC [Google Scholar]
  185. Guppy AE, Rawlings E, Madrigal JA, Amlot PL, Barber LD. 185.  2007. A quantitative assay for Epstein-Barr virus-specific immunity shows interferon-γ producing CD8+ T cells increase during immunosuppression reduction to treat posttransplant lymphoproliferative disease. Transplantation 84:1534–39 [Google Scholar]
  186. Richendollar BG, Tsao RE, Elson P, Jin T, Steinle R. 186.  et al. 2009. Predictors of outcome in post-transplant lymphoproliferative disorder: an evaluation of tumor infiltrating lymphocytes in the context of clinical factors. Leuk. Lymphoma 50:2005–12 [Google Scholar]
  187. Ouyang J, Juszczynski P, Rodig SJ, Green MR, O'Donnell E. 187.  et al. 2011. Viral induction and targeted inhibition of galectin-1 in EBV+ posttransplant lymphoproliferative disorders. Blood 117:4315–22 [Google Scholar]
  188. Durand-Panteix S, Farhat M, Youlyouz-Marfak I, Rouaud P, Ouk-Martin C. 188.  et al. 2012. B7-H1, which represses EBV-immortalized B cell killing by autologous T and NK cells, is oppositely regulated by c-Myc and EBV latency III program at both mRNA and secretory lysosome levels. J. Immunol. 189:181–90 [Google Scholar]
  189. Chen BJ, Chapuy B, Ouyang J, Sun HH, Roemer MG. 189.  et al. 2013. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin. Cancer Res. 19:3462–73 [Google Scholar]
  190. Fox CP, Burns D, Parker AN, Peggs KS, Harvey CM. 190.  et al. 2014. EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era. Bone Marrow Transplant. 49:280–86 [Google Scholar]
  191. Rooney CM, Leen AM, Vera JF, Heslop HE. 191.  2014. T lymphocytes targeting native receptors. Immunol. Rev. 257:39–55 [Google Scholar]
  192. Merlo A, Turrini R, Dolcetti R, Zanovello P, Rosato A. 192.  2011. Immunotherapy for EBV-associated malignancies. Int. J. Hematol. 93:281–93 [Google Scholar]
  193. Doubrovina E, Oflaz-Sozmen B, Prockop SE, Kernan NA, Abramson S. 193.  et al. 2012. Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation. Blood 119:2644–56 [Google Scholar]
  194. Ricciardelli I, Brewin J, Lugthart G, Albon SJ, Pule M, Amrolia PJ. 194.  2013. Rapid generation of EBV-specific cytotoxic T lymphocytes resistant to calcineurin inhibitors for adoptive immunotherapy. Am. J. Transplant. 13:3244–52 [Google Scholar]
  195. Leen AM, Bollard CM, Mendizabal AM, Shpall EJ, Szabolcs P. 195.  et al. 2013. Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation. Blood 121:5113–23 [Google Scholar]
  196. Vickers MA, Wilkie GM, Robinson N, Rivera N, Haque T. 196.  et al. 2014. Establishment and operation of a Good Manufacturing Practice-compliant allogeneic Epstein-Barr virus (EBV)-specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease. Br. J. Haematol. 167:402–10 [Google Scholar]
  197. Icheva V, Kayser S, Wolff D, Tuve S, Kyzirakos C. 197.  et al. 2013. Adoptive transfer of Epstein-Barr virus (EBV) nuclear antigen 1–specific T cells as treatment for EBV reactivation and lymphoproliferative disorders after allogeneic stem-cell transplantation. J. Clin. Oncol. 31:39–48 [Google Scholar]
  198. Diamond C, Taylor TH, Aboumrad T, Anton-Culver H. 198.  2006. Changes in acquired immunodeficiency syndrome-related non-Hodgkin lymphoma in the era of highly active antiretroviral therapy: incidence, presentation, treatment, and survival. Cancer 106:128–35 [Google Scholar]
  199. Polesel J, Clifford GM, Rickenbach M, Dal Maso L, Battegay M. 199.  et al. 2008. Non-Hodgkin lymphoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy. AIDS 22:301–6 [Google Scholar]
  200. Ong KW, Teo M, Lee V, Ong D, Lee A. 200.  et al. 2009. Expression of EBV latent antigens, mammalian target of rapamycin, and tumor suppression genes in EBV-positive smooth muscle tumors: clinical and therapeutic implications. Clin. Cancer Res. 15:5350–58 [Google Scholar]
  201. Lee SP, Chan ATC, Cheung ST, Thomas WA, CroomCarter D. 201.  et al. 2000. CTL control of EBV in nasopharyngeal carcinoma (NPC): EBV-specific CTL responses in the blood and tumors of NPC patients and the antigen-processing function of the tumor cells. J. Immunol. 165:573–82 [Google Scholar]
  202. Fox CP, Haigh TA, Taylor GS, Long HM, Lee SP. 202.  et al. 2010. A novel latent membrane 2 transcript expressed in Epstein-Barr virus-positive NK- and T-cell lymphoproliferative disease encodes a target for cellular immunotherapy. Blood 116:3695–704 [Google Scholar]
  203. Fu T, Voo KS, Wang RF. 203.  2004. Critical role of EBNA1-specific CD4+ T cells in the control of mouse Burkitt lymphoma in vivo. J. Clin. Investig. 114:542–50 [Google Scholar]
  204. Paludan C, Bickham K, Nikiforow S, Tsang ML, Goodman K. 204.  et al. 2002. Epstein-Barr nuclear antigen 1-specific CD4+ Th1 cells kill Burkitt's lymphoma cells. J. Immunol. 169:1593–603 [Google Scholar]
  205. Demachi-Okamura A, Ito Y, Akatsuka Y, Tsujimura K, Morishima Y. 205.  et al. 2008. Epstein–Barr virus nuclear antigen 1-specific CD4+ T cells directly kill Epstein–Barr virus-carrying natural killer and T cells. Cancer Sci. 99:1633–42 [Google Scholar]
  206. Fogg MH, Wirth LJ, Posner M, Wang F. 206.  2009. Decreased EBNA-1-specific CD8+ T cells in patients with Epstein-Barr virus-associated nasopharyngeal carcinoma. PNAS 106:3318–23 [Google Scholar]
  207. Moormann AM, Heller KN, Chelimo K, Embury P, Ploutz-Snyder R. 207.  et al. 2009. Children with endemic Burkitt lymphoma are deficient in EBNA1-specific IFN-γ T cell responses. Int. J. Cancer 124:1721–26 [Google Scholar]
  208. Heller KN, Arrey F, Steinherz P, Portlock C, Chadburn A. 208.  et al. 2008. Patients with Epstein Barr virus-positive lymphomas have decreased CD4+ T-cell responses to the viral nuclear antigen 1. Int. J. Cancer 123:2824–31 [Google Scholar]
  209. Piriou E, van Dort K, Nanlohy NM, van Oers MHJ, Miedema F, van Baarle D. 209.  2005. Loss of EBNA1-specific memory CD4+ and CD8+ T cells in HIV-infected patients progressing to AIDS-related non-Hodgkin lymphoma. Blood 106:3166–74 [Google Scholar]
  210. Chapman ALN, Rickinson AB, Thomas WA, Jarrett RF, Crocker J, Lee SP. 210.  2001. Epstein-Barr virus-specific cytotoxic T lymphocyte responses in the blood and tumor site of Hodgkin's disease patients: implications for a T-cell-based therapy. Cancer Res. 61:6219–26 [Google Scholar]
  211. Lin X, Gudgeon NH, Hui EP, Jia H, Qun X. 211.  et al. 2008. CD4 and CD8 T cell responses to tumour-associated Epstein-Barr virus antigens in nasopharyngeal carcinoma patients. Cancer Immunol. Immunother. 57:963–75 [Google Scholar]
  212. Gandhi MK, Lambley E, Duraiswamy J, Dua U, Smith C. 212.  et al. 2006. Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-cell function in Hodgkin lymphoma patients. Blood 108:2280–89 [Google Scholar]
  213. Niens M, Jarrett RF, Hepkema B, Nolte IM, Diepstra A. 213.  et al. 2007. HLA-A*02 is associated with a reduced risk and HLA-A*01 with an increased risk of developing EBV+ Hodgkin lymphoma. Blood 110:3310–15 [Google Scholar]
  214. Su WH, Hildesheim A, Chang YS. 214.  2013. Human leukocyte antigens and Epstein–Barr virus-associated nasopharyngeal carcinoma: Old associations offer new clues into the role of immunity in infection-associated cancers. Front. Oncol. 3:299 [Google Scholar]
  215. Huang X, Hepkema B, Nolte I, Kushekhar K, Jongsma T. 215.  et al. 2012. HLA-A*02:07 is a protective allele for EBV negative and a susceptibility allele for EBV positive classical Hodgkin lymphoma in China. PLOS ONE 7:e31865 [Google Scholar]
  216. Chetaille B, Bertucci F, Finetti P, Esterni B, Stamatoullas A. 216.  et al. 2009. Molecular profiling of classical Hodgkin lymphoma tissues uncovers variations in the tumor microenvironment and correlations with EBV infection and outcome. Blood 113:2765–3775 [Google Scholar]
  217. Barros MHM, Vera-Lozada G, Soares FA, Niedobitek G, Hassan R. 217.  2012. Tumor microenvironment composition in pediatric classical Hodgkin lymphoma is modulated by age and Epstein-Barr virus infection. Int. J. Cancer 131:1142–52 [Google Scholar]
  218. Morales O, Mrizak D, François V, Mustapha R, Miroux C. 218.  et al. 2014. Epstein–Barr virus infection induces an increase of T regulatory type 1 cells in Hodgkin lymphoma patients. Br. J. Haematol. 166:875–90 [Google Scholar]
  219. Assis MC, Campos AH, Oliveira JS, Soares FA, Silva JM. 219.  et al. 2012. Increased expression of CD4+CD25+FOXP3+ regulatory T cells correlates with Epstein-Barr virus and has no impact on survival in patients with classical Hodgkin lymphoma in Brazil. Med. Oncol. 29:3614–19 [Google Scholar]
  220. Baumforth KRN, Birgersdotter A, Reynolds GM, Wei W, Kapatai G. 220.  et al. 2008. Expression of the Epstein-Barr virus-encoded Epstein-Barr virus nuclear antigen 1 in Hodgkin's lymphoma cells mediates up-regulation of CCL20 and the migration of regulatory T cells. Am. J. Pathol. 173:195–204 [Google Scholar]
  221. Yamamoto R, Nishikori M, Kitawaki T, Sakai T, Hishizawa M. 221.  et al. 2008. PD-1–PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood 111:3220–24 [Google Scholar]
  222. Juszczynski P, Ouyang J, Monti S, Rodig SJ, Takeyama K. 222.  et al. 2007. The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. PNAS 104:13134–39 [Google Scholar]
  223. Green MR, Rodig S, Juszczynski P, Ouyang J, Sinha P. 223.  et al. 2012. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin. Cancer Res. 18:1611–18 [Google Scholar]
  224. Parsonage G, Machado LR, Hui JW, McLarnon A, Schmaler T. 224.  et al. 2012. CXCR6 and CCR5 localize T lymphocyte subsets in nasopharyngeal carcinoma. Am. J. Pathol. 180:1215–22 [Google Scholar]
  225. Yip WK, Abdullah MA, Yusoff SM, Seow HF. 225.  2009. Increase in tumour-infiltrating lymphocytes with regulatory T cell immunophenotypes and reduced ζ-chain expression in nasopharyngeal carcinoma patients. Clin. Exp. Immunol. 155:412–22 [Google Scholar]
  226. Li J, Huang ZF, Xiong G, Mo HY, Qiu F. 226.  et al. 2011. Distribution, characterization, and induction of CD8+ regulatory T cells and IL-17-producing CD8+ T cells in nasopharyngeal carcinoma. J. Transl. Med. 9:189 [Google Scholar]
  227. Klibi J, Niki T, Riedel A, Pioche-Durieu C, Souquere S. 227.  et al. 2009. Blood diffusion and Th1-suppressive effects of galectin-9–containing exosomes released by Epstein-Barr virus–infected nasopharyngeal carcinoma cells. Blood 113:1957–66 [Google Scholar]
  228. Cai MB, Han HQ, Bei JX, Liu CC, Lei JJ. 228.  et al. 2012. Expression of human leukocyte antigen G is associated with prognosis in nasopharyngeal carcinoma. Int. J. Biol. Sci. 8:891–900 [Google Scholar]
  229. 229. Cancer Genome Atlas Res. Netw 2014. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513:202–9 [Google Scholar]
  230. Song HJ, Srivastava A, Lee J, Kim YS, Kim KM. 230.  et al. 2010. Host inflammatory response predicts survival of patients with Epstein-Barr virus–associated gastric carcinoma. Gastroenterology 139:84–92.e2 [Google Scholar]
  231. Strong MJ, Xu G, Coco J, Baribault C, Vinay DS. 231.  et al. 2013. Differences in gastric carcinoma microenvironment stratify according to EBV infection intensity: implications for possible immune adjuvant therapy. PLOS Pathog. 9:e1003341 [Google Scholar]
  232. Louis CU, Straathof K, Bollard CM, Ennamuri S, Gerken C. 232.  et al. 2010. Adoptive transfer of EBV-specific T cells results in sustained clinical responses in patients with locoregional nasopharyngeal carcinoma. J. Immunother. 33:983–90 [Google Scholar]
  233. Chia WK, Teo M, Wang WW, Lee B, Ang SF. 233.  et al. 2014. Adoptive T-cell transfer and chemotherapy in the first-line treatment of metastatic and/or locally recurrent nasopharyngeal carcinoma. Mol. Ther. 22:132–39 [Google Scholar]
  234. Smith C, Tsang J, Beagley L, Chua D, Lee V. 234.  et al. 2012. Effective treatment of metastatic forms of Epstein-Barr virus–associated nasopharyngeal carcinoma with a novel adenovirus-based adoptive immunotherapy. Cancer Res. 72:1116–25 [Google Scholar]
  235. Bollard CM, Gottschalk S, Torrano V, Diouf O, Ku S. 235.  et al. 2014. Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J. Clin. Oncol. 32:798–808 [Google Scholar]
  236. Hui EP, Taylor GS, Jia H, Ma BB, Chan SL. 236.  et al. 2013. Phase I trial of recombinant modified vaccinia Ankara encoding Epstein–Barr viral tumor antigens in nasopharyngeal carcinoma patients. Cancer Res. 73:1676–88 [Google Scholar]
  237. Taylor GS, Jia H, Harrington K, Lee LW, Turner J. 237.  et al. 2014. A recombinant modified vaccinia Ankara vaccine encoding Epstein-Barr virus (EBV) target antigens: a Phase I trial in UK Patients with EBV-positive cancer. Clin. Cancer Res. 20:5009–22 [Google Scholar]
  238. Louis CU, Straathof K, Bollard CM, Gerken C, Huls MH. 238.  et al. 2009. Enhancing the in vivo expansion of adoptively transferred EBV-specific CTL with lymphodepleting CD45 monoclonal antibodies in NPC patients. Blood 113:2442–50 [Google Scholar]
  239. Cohen JI, Fauci AS, Varmus H, Nabel GJ. 239.  2011. Epstein-Barr virus: an important vaccine target for cancer prevention. Sci. Transl. Med. 3:107fs7 [Google Scholar]
  240. Sokal EM, Hoppenbrouwers K, Vandermeulen C, Moutschen M, Leonard P. 240.  et al. 2007. Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy young adults. J. Infect. Dis. 196:1749–53 [Google Scholar]
  241. Sashihara J, Hoshino Y, Bowman JJ, Krogmann T, Burbelo PD. 241.  et al. 2011. Soluble rhesus lymphocryptovirus gp350 protects against infection and reduces viral loads in animals that become infected with virus after challenge. PLOS Pathog. 7:e1002308 [Google Scholar]
  242. Leruez-Ville M, Seng R, Morand P, Boufassa F, Boue F. 242.  et al. 2012. Blood Epstein-Barr virus DNA load and risk of progression to AIDS-related systemic B lymphoma. HIV Med. 13:479–87 [Google Scholar]
  243. Cui X, Cao Z, Sen G, Chattopadhyay G, Fuller DH. 243.  et al. 2013. A novel tetrameric gp350 1–470 as a potential Epstein-Barr virus vaccine. Vaccine 31:3039–45 [Google Scholar]
  244. Adhikary D, Behrends U, Moosmann A, Witter K, Bornkamm GW, Mautner J. 244.  2006. Control of Epstein-Barr virus infection in vitro by T helper cells specific for virion glycoproteins. J. Exp. Med. 203:995–1006 [Google Scholar]
  245. Morgan AJ, Mackett M, Finerty S, Arrand JR, Scullion FT, Epstein MA. 245.  1988. Recombinant vaccinia virus expressing Epstein-Barr virus glycoprotein gp340 protects cottontop tamarins against EB virus-induced malignant lymphomas. J. Med. Virol. 25:189–95 [Google Scholar]
  246. Pavlova S, Feederle R, Gartner K, Fuchs W, Granzow H, Delecluse HJ. 246.  2013. An Epstein-Barr virus mutant produces immunogenic defective particles devoid of viral DNA. J. Virol. 87:2011–22 [Google Scholar]

Data & Media loading...

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error