Encyclopedia of EBV-Encoded Lytic Genes: An Update

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


In addition to latent genes, lytic genes of EBV must also be of extreme significance since propagation of the virus can be achieved only through execution of lytic cycle. Research on EBV lytic genes may thus prevent spreading of the virus and alleviate disorders, such as infectious mononucleosis and oral hairy leukoplakia, which are highly associated with EBV lytic infection. Moreover, recent advancements have been demonstrating that at least several lytic genes are expressed to some extent even during latent state. It is also demonstrated now that upon de novo infection, EBV expresses lytic genes in addition to latent genes before establishment of latency (this phase is called “pre-latent abortive lytic state”). In those cases, lytic genes also play important roles in cell proliferation of EBV-positive cells. However, many lytic gene products have not been identified yet nor studied thoroughly, and even worse, some have been misidentified in the literature. Here, I would like to give a detailed up-to-date review on EBV lytic genes.


EBV; Epstein-Barr virus Gene expression Replication Assembly Capsid Tegument Glycoprotein 


  1. Altmann M, Hammerschmidt W (2005) Epstein-Barr virus provides a new paradigm: a requirement for the immediate inhibition of apoptosis. PLoS Biol 3(12):e404. Scholar
  2. Ariza ME, Glaser R, Kaumaya PT, Jones C, Williams MV (2009) The EBV-encoded dUTPase activates NF-kappa B through the TLR2 and MyD88-dependent signaling pathway. J Immunol 182(2):851–859CrossRefPubMedGoogle Scholar
  3. Aubry V, Mure F, Mariame B, Deschamps T, Wyrwicz LS, Manet E, Gruffat H (2014) Epstein-Barr virus late gene transcription depends on the assembly of a virus-specific preinitiation complex. J Virol 88(21):12825–12838. Scholar
  4. Bhende PM, Seaman WT, Delecluse HJ, Kenney SC (2004) The EBV lytic switch protein, Z, preferentially binds to and activates the methylated viral genome. Nat Genet 36(10):1099–1104. Scholar
  5. Borza CM, Hutt-Fletcher LM (1998) Epstein-Barr virus recombinant lacking expression of glycoprotein gp150 infects B cells normally but is enhanced for infection of epithelial cells. J Virol 72(9):7577–7582PubMedPubMedCentralGoogle Scholar
  6. Chiu YF, Sugden B, Chang PJ, Chen LW, Lin YJ, Lan YC, Lai CH, Liou JY, Liu ST, Hung CH (2012) Characterization and intracellular trafficking of Epstein-Barr virus BBLF1, a protein involved in virion maturation. J Virol 86(18):9647–9655. Scholar
  7. Chiu SH, Wu MC, Wu CC, Chen YC, Lin SF, Hsu JT, Yang CS, Tsai CH, Takada K, Chen MR, Chen JY (2014) Epstein-Barr virus BALF3 has nuclease activity and mediates mature virion production during the lytic cycle. J Virol 88(9):4962–4975. Scholar
  8. Cohen JI, Lekstrom K (1999) Epstein-Barr virus BARF1 protein is dispensable for B-cell transformation and inhibits alpha interferon secretion from mononuclear cells. J Virol 73(9):7627–7632PubMedPubMedCentralGoogle Scholar
  9. Djavadian R, Chiu YF, Johannsen E (2016) An Epstein-Barr virus-encoded protein complex requires an origin of lytic replication in cis to mediate late gene transcription. PLoS Pathog 12(6):e1005718. Scholar
  10. Duarte M, Wang L, Calderwood MA, Adelmant G, Ohashi M, Roecklein-Canfield J, Marto JA, Hill DE, Deng H, Johannsen E (2013) An RS motif within the Epstein-Barr virus BLRF2 tegument protein is phosphorylated by SRPK2 and is important for viral replication. PLoS One 8(1):e53512. Scholar
  11. Farina A, Feederle R, Raffa S, Gonnella R, Santarelli R, Frati L, Angeloni A, Torrisi MR, Faggioni A, Delecluse HJ (2005) BFRF1 of Epstein-Barr virus is essential for efficient primary viral envelopment and egress. J Virol 79(6):3703–3712. Scholar
  12. Feederle R, Kost M, Baumann M, Janz A, Drouet E, Hammerschmidt W, Delecluse HJ (2000) The Epstein-Barr virus lytic program is controlled by the co-operative functions of two transactivators. EMBO J 19(12):3080–3089. Scholar
  13. Feederle R, Neuhierl B, Baldwin G, Bannert H, Hub B, Mautner J, Behrends U, Delecluse HJ (2006) Epstein-Barr virus BNRF1 protein allows efficient transfer from the endosomal compartment to the nucleus of primary B lymphocytes. J Virol 80(19):9435–9443. Scholar
  14. Feederle R, Bannert H, Lips H, Muller-Lantzsch N, Delecluse HJ (2009a) The Epstein-Barr virus alkaline exonuclease BGLF5 serves pleiotropic functions in virus replication. J Virol 83(10):4952–4962. Scholar
  15. Feederle R, Mehl-Lautscham AM, Bannert H, Delecluse HJ (2009b) The Epstein-Barr virus protein kinase BGLF4 and the exonuclease BGLF5 have opposite effects on the regulation of viral protein production. J Virol 83(21):10877–10891. Scholar
  16. Fixman ED, Hayward GS, Hayward SD (1992) trans-acting requirements for replication of Epstein-Barr virus ori-Lyt. J Virol 66(8):5030–5039PubMedPubMedCentralGoogle Scholar
  17. Fixman ED, Hayward GS, Hayward SD (1995) Replication of Epstein-Barr virus oriLyt: lack of a dedicated virally encoded origin-binding protein and dependence on Zta in cotransfection assays. J Virol 69(5):2998–3006PubMedPubMedCentralGoogle Scholar
  18. Gastaldello S, Hildebrand S, Faridani O, Callegari S, Palmkvist M, Di Guglielmo C, Masucci MG (2010) A deneddylase encoded by Epstein-Barr virus promotes viral DNA replication by regulating the activity of cullin-RING ligases. Nat Cell Biol 12(4):351–361. Scholar
  19. Gonnella R, Farina A, Santarelli R, Raffa S, Feederle R, Bei R, Granato M, Modesti A, Frati L, Delecluse HJ, Torrisi MR, Angeloni A, Faggioni A (2005) Characterization and intracellular localization of the Epstein-Barr virus protein BFLF2: interactions with BFRF1 and with the nuclear lamina. J Virol 79(6):3713–3727. Scholar
  20. Gore M, Hutt-Fletcher LM (2009) The BDLF2 protein of Epstein-Barr virus is a type II glycosylated envelope protein whose processing is dependent on coexpression with the BMRF2 protein. Virology 383(1):162–167. Scholar
  21. Gram AM, Oosenbrug T, Lindenbergh MF, Bull C, Comvalius A, Dickson KJ, Wiegant J, Vrolijk H, Lebbink RJ, Wolterbeek R, Adema GJ, Griffioen M, Heemskerk MH, Tscharke DC, Hutt-Fletcher LM, Wiertz EJ, Hoeben RC, Ressing ME (2016) The Epstein-Barr virus glycoprotein gp150 forms an immune-evasive glycan shield at the surface of infected cells. PLoS Pathog 12(4):e1005550. Scholar
  22. Gruffat H, Batisse J, Pich D, Neuhierl B, Manet E, Hammerschmidt W, Sergeant A (2002) Epstein-Barr virus mRNA export factor EB2 is essential for production of infectious virus. J Virol 76(19):9635–9644CrossRefPubMedPubMedCentralGoogle Scholar
  23. Gruffat H, Kadjouf F, Mariame B, Manet E (2012) The Epstein-Barr virus BcRF1 gene product is a TBP-like protein with an essential role in late gene expression. J Virol 86(11):6023–6032. Scholar
  24. Hammerschmidt W, Sugden B (1988) Identification and characterization of oriLyt, a lytic origin of DNA replication of Epstein-Barr virus. Cell 55(3):427–433CrossRefPubMedGoogle Scholar
  25. Heilmann AM, Calderwood MA, Portal D, Lu Y, Johannsen E (2012) Genome-wide analysis of Epstein-Barr virus Rta DNA binding. J Virol 86(9):5151–5164. Scholar
  26. Henson BW, Perkins EM, Cothran JE, Desai P (2009) Self-assembly of Epstein-Barr virus capsids. J Virol 83(8):3877–3890. Scholar
  27. Hislop AD, Ressing ME, van Leeuwen D, Pudney VA, Horst D, Koppers-Lalic D, Croft NP, Neefjes JJ, Rickinson AB, Wiertz EJ (2007) A CD8+ T cell immune evasion protein specific to Epstein-Barr virus and its close relatives in Old World primates. J Exp Med 204(8):1863–1873. Scholar
  28. Janz A, Oezel M, Kurzeder C, Mautner J, Pich D, Kost M, Hammerschmidt W, Delecluse HJ (2000) Infectious Epstein-Barr virus lacking major glycoprotein BLLF1 (gp350/220) demonstrates the existence of additional viral ligands. J Virol 74(21):10142–10152CrossRefPubMedPubMedCentralGoogle Scholar
  29. Jochum S, Moosmann A, Lang S, Hammerschmidt W, Zeidler R (2012) The EBV immunoevasins vIL-10 and BNLF2a protect newly infected B cells from immune recognition and elimination. PLoS Pathog 8(5):e1002704. Scholar
  30. Johannsen E, Luftig M, Chase MR, Weicksel S, Cahir-McFarland E, Illanes D, Sarracino D, Kieff E (2004) Proteins of purified Epstein-Barr virus. Proc Natl Acad Sci U S A 101(46):16286–16291. Scholar
  31. 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. Scholar
  32. Katsumura KR, Maruo S, Takada K (2012) EBV lytic infection enhances transformation of B-lymphocytes infected with EBV in the presence of T-lymphocytes. J Med Virol 84(3):504–510. Scholar
  33. Kawashima D, Kanda T, Murata T, Saito S, Sugimoto A, Narita Y, Tsurumi T (2013) Nuclear transport of Epstein-Barr virus DNA polymerase is dependent on the BMRF1 polymerase processivity factor and molecular chaperone Hsp90. J Virol 87(11):6482–6491. Scholar
  34. Kelly GL, Long HM, Stylianou J, Thomas WA, Leese A, Bell AI, Bornkamm GW, Mautner J, Rickinson AB, Rowe M (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(3):e1000341. Scholar
  35. Kumar GR, Glaunsinger BA (2010) Nuclear import of cytoplasmic poly(A) binding protein restricts gene expression via hyperadenylation and nuclear retention of mRNA. Mol Cell Biol 30(21):4996–5008. Scholar
  36. Lake CM, Hutt-Fletcher LM (2000) Epstein-Barr virus that lacks glycoprotein gN is impaired in assembly and infection. J Virol 74(23):11162–11172CrossRefPubMedPubMedCentralGoogle Scholar
  37. Latif MB, Machiels B, Xiao X, Mast J, Vanderplasschen A, Gillet L (2015) Deletion of murid herpesvirus 4 ORF63 affects the trafficking of incoming capsids toward the nucleus. J Virol 90(5):2455–2472. Scholar
  38. Liu X, Cohen JI (2016) Epstein-Barr virus (EBV) tegument protein BGLF2 promotes EBV reactivation through activation of the p38 mitogen-activated protein kinase. J Virol 90(2):1129–1138. Scholar
  39. Masud HMA, Watanabe T, Yoshida M, Sato Y, Goshima F, Kimura H, Murata T (2017) Epstein-Barr virus BKRF4 gene product is required for efficient progeny production. J Virol 91(23):e00975-17CrossRefPubMedPubMedCentralGoogle Scholar
  40. Meng Q, Hagemeier SR, Fingeroth JD, Gershburg E, Pagano JS, Kenney SC (2010) The Epstein-Barr virus (EBV)-encoded protein kinase, EBV-PK, but not the thymidine kinase (EBV-TK), is required for ganciclovir and acyclovir inhibition of lytic viral production. J Virol 84(9):4534–4542. Scholar
  41. Murata T, Isomura H, Yamashita Y, Toyama S, Sato Y, Nakayama S, Kudoh A, Iwahori S, Kanda T, Tsurumi T (2009) Efficient production of infectious viruses requires enzymatic activity of Epstein-Barr virus protein kinase. Virology 389(1–2):75–81. Scholar
  42. Murata T, Narita Y, Sugimoto A, Kawashima D, Kanda T, Tsurumi T (2013) Contribution of myocyte enhancer factor 2 family transcription factors to BZLF1 expression in Epstein-Barr virus reactivation from latency. J Virol 87(18):10148–10162. Scholar
  43. Murayama K, Nakayama S, Kato-Murayama M, Akasaka R, Ohbayashi N, Kamewari-Hayami Y, Terada T, Shirouzu M, Tsurumi T, Yokoyama S (2009) Crystal structure of Epstein-Barr virus DNA polymerase processivity factor BMRF1. J Biol Chem 284(51):35896–35905. Scholar
  44. Nakayama S, Murata T, Yasui Y, Murayama K, Isomura H, Kanda T, Tsurumi T (2010) Tetrameric ring formation of Epstein-Barr virus polymerase processivity factor is crucial for viral replication. J Virol 84(24):12589–12598. Scholar
  45. Nijmeijer S, Leurs R, Smit MJ, Vischer HF (2010) The Epstein-Barr virus-encoded G protein-coupled receptor BILF1 hetero-oligomerizes with human CXCR4, scavenges Galphai proteins, and constitutively impairs CXCR4 functioning. J Biol Chem 285(38):29632–29641. Scholar
  46. O’Regan KJ, Brignati MJ, Murphy MA, Bucks MA, Courtney RJ (2010) Virion incorporation of the herpes simplex virus type 1 tegument protein VP22 is facilitated by trans-Golgi network localization and is independent of interaction with glycoprotein E. Virology 405(1):176–192. Scholar
  47. Park R, El-Guindy A, Heston L, Lin SF, Yu KP, Nagy M, Borah S, Delecluse HJ, Steitz J, Miller G (2014) Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. PLoS One 9(4):e92593. Scholar
  48. Pavlova S, Feederle R, Gartner K, Fuchs W, Granzow H, Delecluse HJ (2013) An Epstein-Barr virus mutant produces immunogenic defective particles devoid of viral DNA. J Virol 87(4):2011–2022. Scholar
  49. Quinn LL, Williams LR, White C, Forrest C, Zuo J, Rowe M (2016) The missing link in Epstein-Barr virus immune evasion: the BDLF3 gene induces ubiquitination and downregulation of major histocompatibility complex class I (MHC-I) and MHC-II. J Virol 90(1):356–367. Scholar
  50. Rennekamp AJ, Lieberman PM (2011) Initiation of Epstein-Barr virus lytic replication requires transcription and the formation of a stable RNA-DNA hybrid molecule at OriLyt. J Virol 85(6):2837–2850. Scholar
  51. Rowe M, Glaunsinger B, van Leeuwen D, Zuo J, Sweetman D, Ganem D, Middeldorp J, Wiertz EJ, Ressing ME (2007) Host shutoff during productive Epstein-Barr virus infection is mediated by BGLF5 and may contribute to immune evasion. Proc Natl Acad Sci U S A 104(9):3366–3371. Scholar
  52. Saito S, Murata T, Kanda T, Isomura H, Narita Y, Sugimoto A, Kawashima D, Tsurumi T (2013) Epstein-Barr virus deubiquitinase downregulates TRAF6-mediated NF-kappaB signaling during productive replication. J Virol 87(7):4060–4070. Scholar
  53. Schepers A, Pich D, Hammerschmidt W (1993) A transcription factor with homology to the AP-1 family links RNA transcription and DNA replication in the lytic cycle of Epstein-Barr virus. EMBO J 12(10):3921–3929PubMedPubMedCentralCrossRefGoogle Scholar
  54. Sheng W, Decaussin G, Ligout A, Takada K, Ooka T (2003) Malignant transformation of Epstein-Barr virus-negative Akata cells by introduction of the BARF1 gene carried by Epstein-Barr virus. J Virol 77(6):3859–3865CrossRefPubMedPubMedCentralGoogle Scholar
  55. Sinclair AJ (2003) bZIP proteins of human gammaherpesviruses. J Gen Virol 84(Pt 8):1941–1949. Scholar
  56. Song MJ, Hwang S, Wong WH, Wu TT, Lee S, Liao HI, Sun R (2005) Identification of viral genes essential for replication of murine gamma-herpesvirus 68 using signature-tagged mutagenesis. Proc Natl Acad Sci U S A 102(10):3805–3810. Scholar
  57. Su MT, Liu IH, Wu CW, Chang SM, Tsai CH, Yang PW, Chuang YC, Lee CP, Chen MR (2014) Uracil DNA glycosylase BKRF3 contributes to Epstein-Barr virus DNA replication through physical interactions with proteins in viral DNA replication complex. J Virol 88(16):8883–8899. Scholar
  58. Swaminathan S, Hesselton R, Sullivan J, Kieff E (1993) Epstein-Barr virus recombinants with specifically mutated BCRF1 genes. J Virol 67(12):7406–7413PubMedPubMedCentralGoogle Scholar
  59. Tsai K, Thikmyanova N, Wojcechowskyj JA, Delecluse HJ, Lieberman PM (2011) EBV tegument protein BNRF1 disrupts DAXX-ATRX to activate viral early gene transcription. PLoS Pathog 7(11):e1002376. Scholar
  60. Tsurumi T, Daikoku T, Nishiyama Y (1994) Further characterization of the interaction between the Epstein-Barr virus DNA polymerase catalytic subunit and its accessory subunit with regard to the 3′-to-5′ exonucleolytic activity and stability of initiation complex at primer terminus. J Virol 68(5):3354–3363PubMedPubMedCentralGoogle Scholar
  61. Tsurumi T, Kishore J, Yokoyama N, Fujita M, Daikoku T, Yamada H, Yamashita Y, Nishiyama Y (1998) Overexpression, purification and helix-destabilizing properties of Epstein-Barr virus ssDNA-binding protein. J Gen Virol 79(Pt 5):1257–1264. Scholar
  62. Tsurumi T, Fujita M, Kudoh A (2005) Latent and lytic Epstein-Barr virus replication strategies. Rev Med Virol 15(1):3–15. Scholar
  63. Vischer HF, Nijmeijer S, Smit MJ, Leurs R (2008) Viral hijacking of human receptors through heterodimerization. Biochem Biophys Res Commun 377(1):93–97. Scholar
  64. Wang HB, Zhang H, Zhang JP, Li Y, Zhao B, Feng GK, Du Y, Xiong D, Zhong Q, Liu WL, Du H, Li MZ, Huang WL, Tsao SW, Hutt-Fletcher L, Zeng YX, Kieff E, Zeng MS (2015) Neuropilin 1 is an entry factor that promotes EBV infection of nasopharyngeal epithelial cells. Nat Commun 6:6240. Scholar
  65. Watanabe T, Fuse K, Takano T, Narita Y, Goshima F, Kimura H, Murata T (2015a) Roles of Epstein-Barr virus BGLF3.5 gene and two upstream open reading frames in lytic viral replication in HEK293 cells. Virology 483:44–53. Scholar
  66. Watanabe T, Narita Y, Yoshida M, Sato Y, Goshima F, Kimura H, Murata T (2015b) The Epstein-Barr virus BDLF4 gene is required for efficient expression of viral late lytic genes. J Virol 89(19):10120–10124. Scholar
  67. Watanabe T, Tsuruoka M, Narita Y, Katsuya R, Goshima F, Kimura H, Murata T (2015c) The Epstein-Barr virus BRRF2 gene product is involved in viral progeny production. Virology 484:33–40. Scholar
  68. Wei MX, Ooka T (1989) A transforming function of the BARF1 gene encoded by Epstein-Barr virus. EMBO J 8(10):2897–2903PubMedPubMedCentralCrossRefGoogle Scholar
  69. Whitehurst CB, Li G, Montgomery SA, Montgomery ND, Su L, Pagano JS (2015) Knockout of Epstein-Barr virus BPLF1 retards B-cell transformation and lymphoma formation in humanized mice. mBio 6(5):e01574–e01515. Scholar
  70. Yoshida M, Watanabe T, Narita Y, Sato Y, Goshima F, Kimura H, Murata T (2017) The Epstein-Barr virus BRRF1 gene is dispensable for viral replication in HEK293 cells and transformation. Sci Rep 7(1):6044CrossRefPubMedPubMedCentralGoogle Scholar
  71. Zuo J, Currin A, Griffin BD, Shannon-Lowe C, Thomas WA, Ressing ME, Wiertz EJ, Rowe M (2009) The Epstein-Barr virus G-protein-coupled receptor contributes to immune evasion by targeting MHC class I molecules for degradation. PLoS Pathog 5(1):e1000255. Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of VirologyNagoya University Graduate School of MedicineNagoyaJapan
  2. 2.Department of Virology and ParasitologyFujita Health University School of MedicineToyoakeJapan

Personalised recommendations