EBV-Encoded Latent Genes

  • Teru KandaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1045)


Epstein-Barr virus (EBV) is one of the most widespread human pathogens. EBV infection is usually asymptomatic, and it establishes life-long latent infection. EBV latent infection sometimes causes various tumorigenic diseases, such as EBV-related lymphoproliferative diseases, Burkitt lymphomas, Hodgkin lymphomas, NK/T-cell lymphomas, and epithelial carcinomas. EBV-encoded latent genes are set of viral genes that are expressed in latently infected cells. They include virally encoded proteins, noncoding RNAs, and microRNAs. Different latent gene expression patterns are noticed in different types of EBV-infected cells. Viral latent gene products contribute to EBV-mediated B cell transformation and likely contribute to lymphomagenesis and epithelial carcinogenesis as well. Many biological functions of viral latent gene products have been reported, making difficult to understand a whole view of EBV latency. In this review, we will focus on latent gene functions that have been verified by genetic experiments using EBV mutants. We will also summarize how viral latent genes contribute to EBV-mediated B cell transformation, Burkitt lymphomagenesis, and epithelial carcinogenesis.


Latent genes EBNA LMP microRNA Burkitt lymphoma Epithelial carcinogenesis 


  1. Bornkamm GW (2009) Epstein-Barr virus and the pathogenesis of Burkitt's lymphoma: more questions than answers. Int J Cancer 124:1745–1755. CrossRefPubMedGoogle Scholar
  2. Cahir-McFarland ED, Davidson DM, Schauer SL, Duong J, Kieff E (2000) NF-kappa B inhibition causes spontaneous apoptosis in Epstein-Barr virus-transformed lymphoblastoid cells. Proc Natl Acad Sci U S A 97:6055–6060. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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 9:405–411CrossRefPubMedGoogle Scholar
  4. Cancer Genome Atlas Research N (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513:202–209. CrossRefGoogle Scholar
  5. Cohen JI, Wang F, Mannick J, Kieff E (1989) Epstein-Barr virus nuclear protein 2 is a key determinant of lymphocyte transformation. Proc Natl Acad Sci U S A 86:9558–9562CrossRefPubMedPubMedCentralGoogle Scholar
  6. Dawson CW, Eliopoulos AG, Blake SM, Barker R, Young LS (2000) Identification of functional differences between prototype Epstein-Barr virus-encoded LMP1 and a nasopharyngeal carcinoma-derived LMP1 in human epithelial cells. Virology 272:204–217. CrossRefPubMedGoogle Scholar
  7. Dirmeier U, Neuhierl B, Kilger E, Reisbach G, Sandberg ML, Hammerschmidt W (2003) Latent membrane protein 1 is critical for efficient growth transformation of human B cells by epstein-barr virus. Cancer Res 63:2982–2989PubMedGoogle Scholar
  8. Edwards RH, Marquitz AR, Raab-Traub N (2008) Epstein-Barr virus BART microRNAs are produced from a large intron prior to splicing. J Virol 82:9094–9106. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Farrell PJ (2015) Epstein-Barr virus strain variation. Curr Top Microbiol Immunol 390:45–69. CrossRefPubMedGoogle Scholar
  10. Feederle R, Klinke O, Kutikhin A, Poirey R, Tsai MH, Delecluse HJ (2015) Epstein-Barr virus: from the detection of sequence polymorphisms to the recognition of viral types. Curr Top Microbiol Immunol 390:119–148. CrossRefPubMedGoogle Scholar
  11. Gregorovic G et al (2015) Epstein-Barr viruses (EBVs) deficient in EBV-encoded RNAs have higher levels of latent membrane protein 2 RNA expression in Lymphoblastoid cell lines and efficiently establish persistent infections in humanized mice. J Virol 89:11711–11714. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 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 U S A 90:8479–8483CrossRefPubMedPubMedCentralGoogle Scholar
  13. Humme S, Reisbach G, Feederle R, Delecluse HJ, Bousset K, Hammerschmidt W, Schepers A (2003) The EBV nuclear antigen 1 (EBNA1) enhances B cell immortalization several thousandfold. Proc Natl Acad Sci U S A 100:10989–10994. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Johnson RJ, Stack M, Hazlewood SA, Jones M, Blackmore CG, Hu LF, Rowe M (1998) The 30-base-pair deletion in Chinese variants of the Epstein-Barr virus LMP1 gene is not the major effector of functional differences between variant LMP1 genes in human lymphocytes. J Virol 72:4038–4048PubMedPubMedCentralGoogle Scholar
  15. Jones MD, Foster L, Sheedy T, Griffin BE (1984) The EB virus genome in Daudi Burkitt's lymphoma cells has a deletion similar to that observed in a non-transforming strain (P3HR-1) of the virus. EMBO J 3:813–821PubMedPubMedCentralCrossRefGoogle Scholar
  16. Kanda T et al (2013) Interaction between basic residues of Epstein-Barr virus EBNA1 protein and cellular chromatin mediates viral plasmid maintenance. J Biol Chem 288:24189–24199. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Kanda T, Miyata M, Kano M, Kondo S, Yoshizaki T, Iizasa H (2015) Clustered microRNAs of the Epstein-Barr virus cooperatively downregulate an epithelial cell-specific metastasis suppressor. J Virol 89:2684–2697. CrossRefPubMedGoogle Scholar
  18. Kanda T, Furuse Y, Oshitani H, Kiyono T (2016) Highly efficient CRISPR/Cas9-mediated cloning and functional characterization of gastric cancer-derived Epstein-Barr virus strains. J Virol 90:4383–4393. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Kang MS, Kieff E (2015) Epstein-Barr virus latent genes. Exp Mol Med 47:e131. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Kaye KM, Izumi KM, Kieff E (1993) Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc Natl Acad Sci U S A 90:9150–9154CrossRefPubMedPubMedCentralGoogle Scholar
  21. Kelly G, Bell A, Rickinson A (2002) Epstein-Barr virus-associated Burkitt lymphomagenesis selects for downregulation of the nuclear antigen EBNA2. Nat Med 8:1098–1104. CrossRefPubMedGoogle Scholar
  22. Kelly GL, Milner AE, Baldwin GS, Bell AI, Rickinson AB (2006) Three restricted forms of Epstein-Barr virus latency counteracting apoptosis in c-myc-expressing Burkitt lymphoma cells. Proc Natl Acad Sci U S A 103:14935–14940. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Kelly GL 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. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Kieff E, Rickinson AB (2007) In: Knipe DM, Howley PM (eds) Epstein-Barr virus and its replication, Fields virology, vol 2, 5th edn. Lippincott Williams & Wilkins, Philadelphia, pp 2603–2654Google Scholar
  25. Kim DN et al (2013) Characterization of naturally Epstein-Barr virus-infected gastric carcinoma cell line YCCEL1. J Gen Virol 94:497–506. CrossRefPubMedGoogle Scholar
  26. Klinke O, Feederle R, Delecluse HJ (2014) Genetics of Epstein-Barr virus microRNAs. Semin Cancer Biol 26C:52–59. CrossRefGoogle Scholar
  27. Kuzembayeva M, Hayes M, Sugden B (2014) Multiple functions are mediated by the miRNAs of Epstein-Barr virus. Curr Opin Virol 7:61–65. CrossRefPubMedGoogle Scholar
  28. Leight ER, Sugden B (2000) EBNA-1: a protein pivotal to latent infection by Epstein-Barr virus. Rev Med Virol 10:83–100CrossRefPubMedGoogle Scholar
  29. Lin X et al (2015) The Epstein-Barr virus BART miRNA cluster of the M81 strain modulates multiple functions in primary B cells. PLoS Pathog 11:e1005344. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Longnecker R, Miller CL, Miao XQ, Tomkinson B, Kieff E (1993) The last seven transmembrane and carboxy-terminal cytoplasmic domains of Epstein-Barr virus latent membrane protein 2 (LMP2) are dispensable for lymphocyte infection and growth transformation in vitro. J Virol 67:2006–2013PubMedPubMedCentralGoogle Scholar
  31. Mannick JB, Cohen JI, Birkenbach M, Marchini A, Kieff E (1991) The Epstein-Barr virus nuclear protein encoded by the leader of the EBNA RNAs is important in B-lymphocyte transformation. J Virol 65:6826–6837PubMedPubMedCentralGoogle Scholar
  32. Maruo S, Zhao B, Johannsen E, Kieff E, Zou J, Takada K (2011) Epstein-Barr virus nuclear antigens 3C and 3A maintain lymphoblastoid cell growth by repressing p16INK4A and p14ARF expression. Proc Natl Acad Sci U S A 108:1919–1924. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Minamitani T et al (2015) Evasion of affinity-based selection in germinal centers by Epstein-Barr virus LMP2A. Proc Natl Acad Sci U S A 112:11612–11617. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Munz C (ed) (2015a) Epstein Barr virus volume 1 one herpes virus: many diseases, vol 390. Curr Top Microbiol.
  35. Munz C (ed) (2015b) Epstein Barr virus volume 2 one herpes virus: many diseases, vol 390. Curr Top Microbiol.
  36. Nanbo A, Takada K (2002) The role of Epstein-Barr virus-encoded small RNAs (EBERs) in oncogenesis. Rev Med Virol 12:321–326. CrossRefPubMedGoogle Scholar
  37. Nitta T, Chiba A, Yamamoto N, Yamaoka S (2004) Lack of cytotoxic property in a variant of Epstein-Barr virus latent membrane protein-1 isolated from nasopharyngeal carcinoma. Cell Signal 16:1071–1081. CrossRefPubMedGoogle Scholar
  38. Oudejans JJ et al (1995) BHRF1, the Epstein-Barr virus (EBV) homologue of the BCL-2 protooncogene, is transcribed in EBV-associated B-cell lymphomas and in reactive lymphocytes. Blood 86:1893–1902PubMedGoogle Scholar
  39. Palser AL et al (2015) Genome diversity of Epstein-Barr virus from multiple tumor types and normal infection. J Virol 89:5222–5237. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Paschos K, Smith P, Anderton E, Middeldorp JM, White RE, Allday MJ (2009) Epstein-barr virus latency in B cells leads to epigenetic repression and CpG methylation of the tumour suppressor gene Bim. PLoS Pathog 5:e1000492. CrossRefPubMedPubMedCentralGoogle Scholar
  41. Pfeffer S et al (2004) Identification of virus-encoded microRNAs. Science 304:734–736CrossRefPubMedGoogle Scholar
  42. 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:e1004561. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 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 22:257–267CrossRefPubMedGoogle Scholar
  44. Rabson M, Gradoville L, Heston L, Miller G (1982) Non-immortalizing P3J-HR-1 Epstein-Barr virus: a deletion mutant of its transforming parent, Jijoye. J Virol 44:834–844PubMedPubMedCentralGoogle Scholar
  45. Renzette N et al (2014) Epstein-Barr virus latent membrane protein 1 genetic variability in peripheral blood B cells and oropharyngeal fluids. J Virol 88:3744–3755. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Rickinson AB, Kieff E (2007) In: Knipe M, Howley PM (eds) Epstein-Barr virus, Fields virology, vol 2, 5th edn. Lippincott Williams & Wilkins, Philadelphia, pp 2655–2700Google Scholar
  47. Robertson ES, Tomkinson B, Kieff E (1994) An Epstein-Barr virus with a 58-kilobase-pair deletion that includes BARF0 transforms B lymphocytes in vitro. J Virol 68:1449–1458PubMedPubMedCentralGoogle Scholar
  48. Rowe M, Kelly GL, Bell AI, Rickinson AB (2009) Burkitt's lymphoma: the Rosetta Stone deciphering Epstein-Barr virus biology. Semin Cancer Biol 19:377–388. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Sears J, Ujihara M, Wong S, Ott C, Middeldorp J, Aiyar A (2004) The amino terminus of Epstein-Barr virus (EBV) nuclear antigen 1 contains AT hooks that facilitate the replication and partitioning of latent EBV genomes by tethering them to cellular chromosomes. J Virol 78:11487–11505. CrossRefPubMedPubMedCentralGoogle Scholar
  50. Seto E, Moosmann A, Gromminger 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:e1001063CrossRefPubMedPubMedCentralGoogle Scholar
  51. Shire K, Ceccarelli DF, Avolio-Hunter TM, Frappier L (1999) EBP2, a human protein that interacts with sequences of the Epstein-Barr virus nuclear antigen 1 important for plasmid maintenance. J Virol 73:2587–2595PubMedPubMedCentralGoogle Scholar
  52. Skalska L, White RE, Franz M, Ruhmann M, Allday MJ (2010) Epigenetic repression of p16(INK4A) by latent Epstein-Barr virus requires the interaction of EBNA3A and EBNA3C with CtBP. PLoS Pathog 6:e1000951. CrossRefPubMedPubMedCentralGoogle Scholar
  53. Swaminathan S, Tomkinson B, Kieff E (1991) Recombinant Epstein-Barr virus with small RNA (EBER) genes deleted transforms lymphocytes and replicates in vitro. Proc Natl Acad Sci U S A 88:1546–1550CrossRefPubMedPubMedCentralGoogle Scholar
  54. Thorley-Lawson DA, Allday MJ (2008) The curious case of the tumour virus: 50 years of Burkitt's lymphoma. Nat Rev Microbiol 6:913–924. CrossRefPubMedGoogle Scholar
  55. Tomkinson B, Kieff E (1992) Use of second-site homologous recombination to demonstrate that Epstein-Barr virus nuclear protein 3B is not important for lymphocyte infection or growth transformation in vitro. J Virol 66:2893–2903PubMedPubMedCentralGoogle Scholar
  56. Tomkinson B, Robertson E, Kieff E (1993) Epstein-Barr virus nuclear proteins EBNA-3A and EBNA-3C are essential for B-lymphocyte growth transformation. J Virol 67:2014–2025PubMedPubMedCentralGoogle Scholar
  57. Tsai MH et al (2013) Spontaneous lytic replication and epitheliotropism define an Epstein-Barr virus strain found in carcinomas. Cell Rep 5:458–470. CrossRefPubMedGoogle Scholar
  58. Tsang CM et al (2012) Cyclin D1 overexpression supports stable EBV infection in nasopharyngeal epithelial cells. Proc Natl Acad Sci U S A 109:E3473–E3482. CrossRefPubMedPubMedCentralGoogle Scholar
  59. Tsao SW, Tsang CM, To KF, Lo KW (2015) The role of Epstein-Barr virus in epithelial malignancies. J Pathol 235:323–333. CrossRefPubMedGoogle Scholar
  60. Tzellos S et al (2014) A single amino acid in EBNA-2 determines superior B lymphoblastoid cell line growth maintenance by Epstein-Barr virus type 1 EBNA-2. J Virol 88:8743–8753. CrossRefPubMedPubMedCentralGoogle Scholar
  61. Walling DM, Brown AL, Etienne W, Keitel WA, Ling PD (2003) Multiple Epstein-Barr virus infections in healthy individuals. J Virol 77:6546–6550CrossRefPubMedPubMedCentralGoogle Scholar
  62. Wang D, Liebowitz D, Kieff E (1985) An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell 43:831–840CrossRefGoogle Scholar
  63. Watanabe A, Maruo S, Ito T, Ito M, Katsumura KR, Takada K (2010) Epstein-Barr virus-encoded Bcl-2 homologue functions as a survival factor in Wp-restricted Burkitt lymphoma cell line P3HR-1. J Virol 84:2893–2901. CrossRefPubMedGoogle Scholar
  64. White RE et al (2012) EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors. J Clin Invest 122:1487–1502. CrossRefPubMedPubMedCentralGoogle Scholar
  65. Yajima M, Kanda T, Takada K (2005) Critical role of Epstein-Barr virus (EBV)-encoded RNA in efficient EBV-induced B-lymphocyte growth transformation. J Virol 79:4298–4307. CrossRefPubMedPubMedCentralGoogle Scholar
  66. Young LS, Rickinson AB (2004) Epstein-Barr virus: 40 years on. Nat Rev Cancer 4:757–768. CrossRefPubMedGoogle Scholar
  67. Young LS, Yap LF, Murray PG (2016) Epstein-Barr virus: more than 50 years old and still providing surprises. Nat Rev Cancer 16:789–802. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Division of Microbiology, Faculty of MedicineTohoku medical and Pharmaceutical UniversitySendaiJapan

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