Abstract
Epstein-Barr virus (EBV) is an ancient virus and has probably coevolved with its different hosts over the last 90–100 million years. With the ability to establish lifelong latency and intermittent reactivation after primary infection and with limited clinical symptoms in the majority of infected individuals, EBV has become ubiquitous in all human populations. The virus has been implicated in the development of a wide variety of benign and malignant diseases, although no satisfactory explanation of its role in the pathogenesis of these disorders has been still provided. In this chapter, we will uncover the immune and viral mechanisms that establish whether EBV may coexist harmoniously with the immune system as in most of individuals or whether infection could result in one of the many EBV-associated malignancies. A brief description of such diseases is also added.
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Ambrosio MR, Mastrogiulio MG, Barone A, Rocca BJ, Gallo C, Lazzi S, Leoncini L, Bellan C (2013) Lymphoepithelial-like carcinoma of the parotid gland: a case report and a brief review of the western literature. Diagn Pathol 8:115
Ambrosio MR, De Falco G, Gozzetti A, Rocca BJ, Amato T, Mourmouras V, Gazaneo S, Mundo L, Candi V, Piccaluga PP, Cusi MG, Leoncini L, Lazzi S (2014) Plasmablastic transformation of a pre-existing plasmacytoma: a possible role for reactivation of Epstein Barr virus infection. Haematologica 99(11):e235–e237
Ambrosio MR, Navari M, Di Lisio L, Leon EA, Onnis A, Gazaneo S, Mundo L, Ulivieri C, Gomez G, Lazzi S, Piris MA, Leoncini L, De Falco G (2014) The Epstein Barr-encoded BART-6-3p microRNA affects regulation of cell growth and immuno response in Burkitt lymphoma. Infect Agent Cancer 9:12
Amoroso R, Fitzsimmons L, Thomas WA, Kelly GL, Rowe M, Bell AI (2011) Quantitative studies of Epstein-Barr virus-encoded microRNAs provide novel insights into their regulation. J Virol 85(2):996–1010
Baer R, Bankier AT, Biggin MD, Deininger PL, Farrell PJ, Gibson TJ, Hatfull G, Hudson GS, Satchwell SC, Séguin C et al (1984) DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature 310(5974):207–211
Burkitt D (1962) A “tumour safari” in East and Central Africa. Br J Cancer 16:379–386
Cai X, Schäfer A, Lu S, Bilello JP, Desrosiers RC, Edwards R, Raab-Traub N, Cullen BR (2006) Epstein-Barr virus microRNAs are evolutionarily conserved and differentially expressed. PLoS Pathog 2(3), e23
Canaan A, Haviv I, Urban AE, Schulz VP, Hartman S, Zhang Z, Palejev D, Deisseroth AB, Lacy J, Snyder M, Gerstein M, Weissman SM (2009) EBNA1 regulates cellular gene expression by binding cellular promoters. Proc Natl Acad Sci U S A 106(52):22421–22426
Cancian L, Bosshard R, Lucchesi W, Karstegl CE, Farrell PJ (2011) C-terminal region of EBNA-2 determines the superior transforming ability of type 1 Epstein-Barr virus by enhanced gene regulation of LMP-1 and CXCR7. PLoS Pathog 7(7), e1002164
Carbone A, Cesarman E, Gloghini A, Drexler HG (2010) Understanding pathogenetic aspects and clinical presentation of primary effusion lymphoma through its derived cell lines. AIDS 24(4):479–490
Cheng N, Hui DY, Liu Y, Zhang NN, Jiang Y, Han J, Li HG, Ding YG, Du H, Chen JN, Shao CK (2015) Is gastric lymphoepithelioma-like carcinoma a special subtype of EBV-associated gastric carcinoma? New insight based on clinicopathological features and EBV genome polymorphisms. Gastric Cancer 18(2):246–255
Crawford DH, Macsween KF, Higgins CD, Thomas R, McAulay K, Williams H, Harrison N, Reid S, Conacher M, Douglas J, Swerdlow AJ (2006) A cohort study among university students: identification of risk factors for Epstein-Barr virus seroconversion and infectious mononucleosis. Clin Infect Dis 43(3):276–282
Croce CM (2009) Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 10(10):704–714
De Falco G, Antonicelli G, Onnis A, Lazzi S, Bellan C, Leoncini L (2009) Role of EBV in microRNA dysregulation in Burkitt lymphoma. Semin Cancer Biol 19(6):401–406
Delgado-Eckert E, Shapiro M (2011) A model of host response to a multi-stage pathogen. J Math Biol 63(2):201–227
Delecluse HJ, Feederle R, O’Sullivan B, Taniere P (2007) Epstein Barr virus-associated tumours: an update for the attention of the working pathologist. J Clin Pathol 60(12):1358–1364
Dittmer DP (2014) Not like a wrecking ball: EBV fine-tunes MYC lymphomagenesis. Blood 123(4):460–461
Dunleavy K, Roschewski M, Wilson WH (2012) Lymphomatoid granulomatosis and other Epstein-Barr virus associated lymphoproliferative processes. Curr Hematol Malig Rep 7:208–215
Epstein MA, Achong BG, Barr YM (1964) Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet 1(7335):702–703
Fish K, Chen J, Longnecker R (2014) Epstein-Barr virus latent membrane protein 2A enhances MYC-driven cell cycle progression in a mouse model of B lymphoma. Blood 123(4):530–540
Frappier L (2012) Contributions of Epstein-Barr nuclear antigen 1 (EBNA1) to cell immortalization and survival. Viruses 4(9):1537–1547
Grömminger S, Mautner J, Bornkamm GW (2012) Burkitt lymphoma: the role of Epstein–Barr virus revisited. Br J Haematol 156:719–729
Hatfull G et al (1988) Sequence analysis of Raji Epstein-Barr virus DNA. Virology 164(2):334–340
Hatton OL, Harris-Arnold A, Schaffert S, Krams SM, Martinez OM (2014) The interplay between Epstein-Barr virus and B lymphocytes: implications for infection, immunity, and disease. Immunol Res 58(2–3):268–276
Hauptman N, Glavac D (2013) MicroRNAs and long non-coding RNAs: prospects in diagnostics and therapy of cancer. Radiol Oncol 47(4):311–318
Hertle ML, Popp C, Petermann S, Maier S, Kremmer E, Lang R, Mages J, Kempkes B (2009) Differential gene expression patterns of EBV infected EBNA-3A positive and negative human B lymphocytes. PLoS Pathog 5(7), e1000506
Hjalgrim H, Friborg J, Melbye M (2007) The epidemiology of EBV and its association with malignant disease. In: CBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health, Arvin A, Campadelli-Fiume G, Mocarski E et al (eds) Human herpesviruses: biology, therapy, and immunoprophylaxis. Cambridge University Press, Cambridge
Holmes RD, Sokol RJ (2002) Epstein-Barr virus and post-transplant lymphoproliferative disease. Pediatr Transplant 6(6):456–464
Hong GK, Gulley ML, Feng WH, Delecluse HJ, Holley-Guthrie E, Kenney SC (2005) Epstein-Barr virus lytic infection contributes to lymphoproliferative disease in a SCID mouse model. J Virol 79(22):13993–14003
Hussein K, Rath B, Ludewig B, Kreipe H, Jonigk D (2014) Clinico-pathological characteristics of different types of immunodeficiency-associated smooth muscle tumours. Eur J Cancer 50(14):2417–2424
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(5):4481–4484
Kalla M, Schmeinck A, Bergbauer M, Pich D, Hammerschmidt W (2010) AP-1 homolog BZLF1 of Epstein-Barr virus has two essential functions dependent on the epigenetic state of the viral genome. Proc Natl Acad Sci U S A 107(2):850–855
Kalla M, Hammerschmidt W (2012) Human B cells on their route to latent infection–early but transient expression of lytic genes of Epstein-Barr virus. Eur J Cell Biol 91(1):65–69
Kalla M, Göbel C, Hammerschmidt W (2012) The lytic phase of epstein-barr virus requires a viral genome with 5-methylcytosine residues in CpG sites. J Virol 86(1):447–458
Kanamori M, Watanabe S, Honma R, Kuroda M, Imai S, Takada K, Yamamoto N, Nishiyama Y, Kawaguchi Y (2004) Epstein-Barr virus nuclear antigen leader protein induces expression of thymus- and activation-regulated chemokine in B cells. J Virol 78(8):3984–3993
Kato H, Karube K, Yamamoto K, Takizawa J, Tsuzuki S, Yatabe Y, Kanda T, Katayama M, Ozawa Y, Ishitsuka K, Okamoto M, Kinoshita T, Ohshima K, Nakamura S, Morishima Y, Seto M (2014) Gene expression profiling of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly reveals alterations of characteristic oncogenetic pathways. Cancer Sci 105(5):537–544
Kenney SC, Mertz JE (2014) Regulation of the latent-lytic switch in Epstein-Barr virus. Semin Cancer Biol 26:60–68
Laichalk LL, Thorley-Lawson DA (2005) Terminal differentiation into plasma cells initiates the replicative cycle of Epstein-Barr virus in vivo. J Virol 79(2):1296–1307
Lambert SL, Martinez OM (2007) Latent membrane protein 1 of EBV activates phosphatidylinositol 3-kinase to induce production of IL-10. J Immunol 179(12):8225–8234
Li Y, Webster-Cyriaque J, Tomlinson CC, Yohe M, Kenney S (2004) Fatty acid synthase expression is induced by the Epstein-Barr virus immediate-early protein BRLF1 and is required for lytic viral gene expression. J Virol 78(8):4197–4206
Li L, Guo L, Tao Y, Zhou S, Wang Z, Luo W, Hu D, Li Z, Xiao L, Tang M, Yi W, Tsao SW, Cao Y (2007) Latent membrane protein 1 of Epstein-Barr virus regulates p53 phosphorylation through MAP kinases. Cancer Lett 255(2):219–231
Libri V, Miesen P, van Rij RP, Buck AH (2013) Regulation of microRNA biogenesis and turnover by animals and their viruses. Cell Mol Life Sci 70(19):3525–3544
Linnerbauer S, Behrends U, Adhikary D, Witter K, Bornkamm GW, Mautner J (2014) Virus and autoantigen-specific CD4+ T cells are key effectors in a SCID mouse model of EBV-associated post-transplant lymphoproliferative disorders. PLoS Pathog 10(5), e1004068
Lopes LF, Ruiz Miyazawa KW, de Almeida ER, Serafim KG, de Almeida Gualtieri K, Costa IC, Felipe I, Pavanelli WR, Watanabe MA (2013) Epstein-Barr virus (EBV) microRNAs: involvement in cancer pathogenesis and immunopathology. Int Rev Immunol 32(3):271–281
Maier S, Staffler G, Hartmann A, Höck J, Henning K, Grabusic K, Mailhammer R, Hoffmann R, Wilmanns M, Lang R, Mages J, Kempkes B (2006) Cellular target genes of Epstein-Barr virus nuclear antigen 2. J Virol 80(19):9761–9771
Mannucci S, Luzzi A, Carugi A, Gozzetti A, Lazzi S, Malagnino V, Simmonds M, Cusi MG, Leoncini L, van den Bosch CA, De Falco G (2012) EBV reactivation and chromosomal polysomies: euphorbia tirucalli as a possible cofactor in endemic Burkitt lymphoma. Adv Hematol 2012:149780
McClellan MJ, Khasnis S, Wood CD, Palermo RD, Schlick SN, Kanhere AS, Jenner RG, West MJ (2012) Downregulation of integrin receptor-signaling genes by Epstein-Barr virus EBNA 3Cvia promoter-proximal and -distal binding elements. J Virol 86(9):5165–5178
Morales O, Mrizak D, François V, Mustapha R, Miroux C, Depil S, Decouvelaere AV, Lionne-Huyghe P, Auriault C, de Launoit Y, Pancré V, Delhem N (2014) Epstein-Barr virus infection induces an increase of T regulatory type 1 cells in Hodgkin lymphoma patients. Br J Haematol 166(6):875–890
Morscio J, Dierickx D, Nijs J, Verhoef G, Bittoun E, Vanoeteren X, Wlodarska I, Sagaert X, Tousseyn T (2014) Clinicopathologic comparison of plasmablastic lymphoma in HIV-positive, immunocompetent, and posttransplant patients: single-center series of 25 cases and meta-analysis of 277 reported cases. Am J Surg Pathol 38(7):875–886
Nana-Sinkam SP, Croce CM (2011) Non-coding RNAs in cancer initiation and progression and as novel biomarkers. Mol Oncol 5(6):483–491
Navari M, Fuligni F, Laginestra MA, Etebari M, Ambrosio MR, Sapienza MR, Rossi M, De Falco G, Gibellini D, Tripodo C, Pileri SA, Leoncini L, Piccaluga PP (2014) Molecular signature of Epstein Barr virus-positive Burkitt lymphoma and post-transplant lymphoproliferative disorder suggest different roles for Epstein Barr virus. Front Microbiol 5:728
Nishikawa J, Yoshiyama H, Iizasa H, Kanehiro Y, Nakamura M, Nishimura J, Saito M, Okamoto T, Sakai K, Suehiro Y, Yamasaki T, Oga A, Yanai H, Sakaida I (2014) Epstein-barr virus in gastric carcinoma. Cancers (Basel) 6(4):2259–2274
Onnis A, Navari M, Antonicelli G, Morettini F, Mannucci S, De Falco G, Vigorito E, Leoncini L (2012) Epstein-Barr nuclear antigen 1 induces expression of the cellular microRNA hsa-miR-127 and impairing B-cell differentiation in EBV-infected memory B cells. New insights into the pathogenesis of Burkitt lymphoma. Blood Cancer J 2, e84
Peng R, Moses SC, Tan J, Kremmer E, Ling PD (2005) The Epstein-Barr virus EBNA-LP protein preferentially coactivates EBNA2-mediated stimulation of latent membrane proteins expressed from the viral divergent promoter. J Virol 79(7):4492–4505
Ocheni S, Kroeger N, Zabelina T, Sobottka I, Ayuk F, Wolschke C, Muth A, Lellek H, Petersen L, Erttmann R, Kabisch H, Zander AR, Bacher U (2008) EBV reactivation and post transplant lymphoproliferative disorders following allogeneic SCT. Bone Marrow Transplant 42(3):181–186
Pratt ZL, Kuzembayeva M, Sengupta S, Sugden B (2009) The microRNAs of Epstein-Barr Virus are expressed at dramatically differing levels among cell lines. Virology 386(2):387–397
Qiu J, Smith P, Leahy L, Thorley-Lawson DA (2015) The Epstein-Barr virus encoded BART miRNAs potentiate tumor growth in vivo. PLoS Pathog 11(1), e1004561
Rastelli J, Hömig-Hölzel C, Seagal J, Müller W, Hermann AC, Rajewsky K, Zimber-Strobl U (2008) LMP1 signaling can replace CD40 signaling in B cells in vivo and has unique features of inducing class-switch recombination to IgG1. Blood 111(3):1448–1455
Rezk SA, Weiss LM (2007) Epstein-Barr virus-associated lymphoproliferative disorders. Hum Pathol 38(9):1293–1304
Rickinson AB (2014) Co-infections, inflammation and oncogenesis: future directions for EBV research. Semin Cancer Biol 26:99–115
Robertson ES (2010) Epstein-Barr virus: latency and transformation. Caister Academic Press, Wymondham
Roughan JE, Thorley-Lawson DA (2009) The intersection of Epstein-Barr virus with the germinal center. J Virol 83(8):3968–3976
Rowe M, Fitzsimmons L, Bell AI (2014) Epstein-Barr virus and Burkitt lymphoma. Chin J Cancer 33(12):609–619
Sano H, Nagata K, Kato K, Kanai K, Yamamoto K, Okuno K, Kuwamoto S, Higaki-Mori H, Sugihara H, Kato M, Murakami I, Kanzaki S, Hayashi K (2013) EBNA-2 -deleted Epstein-Barr virus from P3HR-1 can infect rabbits with lower efficiency than prototype Epstein-Barr virus from B95-8. Intervirology 56(2):114–121
Seto E, Moosmann A, Grömminger S, Walz N, Grundhoff A, Hammerschmidt W (2010) Micro RNAs of Epstein-Barr virus promote cell cycle progression and prevent apoptosis of primary human B cells. PLoS Pathog 6(8), e1001063
Sixbey JW, Nedrud JG, Raab-Traub N, Hanes RA, Pagano JS (1984) Epstein-Barr virus replication in oropharyngeal epithelial cells. N Engl J Med 310(19):1225–1230
Soderberg-Nauclér C, Rahbar A, Stragliotto G (2013) Survival in patients with Glioblastoma receiving valganciclovir. N Engl J Med 369(10):985–986
Sompallae R, Callegari S, Kamranvar SA, Masucci MG (2010) Transcription profiling of Epstein-Barr virus nuclear antigen (EBNA)-1 expressing cells suggests targeting of chromatin remodeling complexes. PLoS One 5(8), e12052
Sugita Y, Terasaki M, Niino D, Ohshima K, Fumiko A, Shigemori M, Sato Y, Asano N (2010) Epstein-Barr virus-associated primary central nervous system lymphomas in immunocompetent elderly patients: analysis for latent membrane protein-1 oncogene deletion and EBNA-2 strain typing. J Neurooncol 100(2):271–279
Takakuwa T, Tresnasari K, Rahadiani N, Miwa H, Daibata M, Aozasa K (2008) Cell origin of pyothorax-associated lymphoma: a lymphoma strongly associated with Epstein-Barr virus infection. Leukemia 22(3):620–627
Taylor GS, Blackbourn DJ (2011) Infectious agents in human cancers: lessons in immunity and immunomodulation from gammaherpesviruses EBV and KSHV. Cancer Lett 305(2):263–278
Teras LR, Rollison DE, Pawlita M, Michel A, Brozy J, de Sanjose S, Blase JL, Gapstur SM (2015) Epstein-Barr virus and risk of non-Hodgkin lymphoma in the cancer prevention study-II and a meta-analysis of serologic studies. Int J Cancer 136(1):108–116
Thornburg NJ, Kulwichit W, Edwards RH, Shair KH, Bendt KM, Raab-Traub N (2006) LMP1 signaling and activation of NF-kappaB in LMP1 transgenic mice. Oncogene 25(2):288–297
Thompson MP, Kurzrock R (2004) Epstein-Barr virus and cancer. Clin Cancer Res 10(3):803–821
Thorley-Lawson DA (2001) Epstein-Barr virus: exploiting the immune system. Nat Rev Immunol 1(1):75–82
Thorley-Lawson DA, Allday MJ (2008) The curious case of the tumour virus: 50 years of Burkitt’s lymphoma. Nat Rev Microbiol 6(12):913–924
Tselis A, Jenson HB (2006) Epstein-Barr virus (infectious disease and therapy). Informa Healthcare, New York, New York. ISBN 0824754255. 2006
Yang L, Aozasa K, Oshimi K, Takada K (2004) Epstein-Barr virus (EBV)-encoded RNA promotes growth of EBV-infected T cells through interleukin-9 induction. Cancer Res 64(15):5332–5337
Yenamandra SP, Sompallae R, Klein G, Kashuba E (2009) Comparative analysis of the Epstein-Barr virus encoded nuclear proteins of EBNA-3 family. Comput Biol Med 39(11):1036–1042
Young LS, Murray PG (2003) Epstein-Barr virus and oncogenesis: from latent genes to tumours. Oncogene 22(33):5108–5121
Young LS, Dawson CW (2014) Epstein-Barr virus and nasopharyngeal carcinoma. Chin J Cancer 33(12):581–590
Vereide D, Sugden B (2010) Insights into the evolution of lymphomas induced by Epstein-Barr virus. Adv Cancer Res 108:1–19
Vereide DT, Sugden B (2011) Lymphomas differ in their dependence on Epstein-Barr virus. Blood 117(6):1977–1985
Vockerodt M, Cader FZ, Shannon-Lowe C, Murray P (2014) Epstein-Barr virus and the origin of Hodgkin lymphoma. Chin J Cancer 33(12):591–597
Vockerodt M, Yap LF, Shannon-Lowe C, Curley H, Wei W, Vrzalikova K, Murray PG (2015) The Epstein-Barr virus and the pathogenesis of lymphoma. J Pathol 235(2):312–322
Wasil LR, Tomaszewski MJ, Hoji A, Rowe DT (2013) The effect of Epstein-Barr virus latent membrane protein 2 expression on the kinetics of early B cell infection. PLoS One 8(1), e54010
Wang RC, Chang ST, Hsieh YC, Huang WT, Hsu JD, Tseng CE, Wang MC, Hwang WS, Wang J, Chuang SS (2014) Spectrum of Epstein-Barr virus-associated T-cell lymphoproliferative disorder in adolescents and young adults in Taiwan. Int J Clin Exp Pathol 7(5):2430–2437
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(11), e13979
Zhang B, Kracker S, Yasuda T, Casola S, Vanneman M, Hömig-Hölzel C, Wang Z, Derudder E, Li S, Chakraborty T, Cotter SE, Koyama S, Currie T, Freeman GJ, Kutok JL, Rodig SJ, Dranoff G, Rajewsky K (2012) Immune surveillance and therapy of lymphomas driven by Epstein-Barr virus protein LMP1 in a mouse model. Cell 148(4):739–751
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Ambrosio, M.R., Leoncini, L. (2015). Epidemiology of Epstein-Barr Virus and Mechanisms of Carcinogenesis. In: Droz, JP., Carme, B., Couppié, P., Nacher, M., Thiéblemont, C. (eds) Tropical Hemato-Oncology. Springer, Cham. https://doi.org/10.1007/978-3-319-18257-5_15
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