Epstein–Barr Virus


Epstein–Barr virus (EBV) is a ubiquitous gamma herpesvirus aetiologically linked to different lymphoid and epithelial malignancies and a number of systemic autoimmune diseases. The virus has a unique ability to transform resting B lymphocytes in vitro by expressing a set of latent genes, subsets of which are present in EBV‐associated tumours. EBV exploits the physiology of normal B‐cell differentiation to persist within the memory B‐cell pool of the immunocompetent host with strong T‐cell responses important for controlling EBV infection. Immunosuppressed transplant recipients and human immunodeficiency virus (HIV)‐infected individuals are at increased risk of developing EBV‐transformed B‐cell proliferations which often present as monoclonal non‐Hodgkin lymphomas. The major EBV‐associated tumours (Burkitt lymphoma, Hodgkin lymphoma and nasopharyngeal carcinoma) show restricted forms of latent viral gene expression reflecting a more complex pathogenesis involving additional cofactors. A number of pharmacological and immunotherapeutic approaches are being developed to treat or prevent these EBV‐associated tumours.

Key Concepts

  • Epstein–Barr virus (EBV) infection is implicated in the aetiology of several different lymphoid and epithelial malignancies, as well as a number of systemic autoimmune diseases.
  • EBV exploits the physiology of normal B‐cell differentiation to persist within the memory B‐cell pool of the immunocompetent host.
  • EBV‐encoded latent genes induce B‐cell transformation in vitro by altering cellular gene transcription and constitutively activating key cell signalling pathways.
  • Immunosuppressed transplant patients are at risk of developing EBV‐transformed B‐cell proliferations presenting as B‐cell lymphomas.
  • Other EBV‐associated tumours display more restricted forms of latent gene expression, reflecting more complex pathogenesis involving additional cofactors.
  • EBV sequence variation may reflect disease risk.
  • Pharmacological and immunotherapeutic approaches are being developed to treat or prevent EBV‐associated tumours.
  • More direct vaccine approaches are being examined for the treatment and prevention of EBV‐associated diseases.

Keywords: herpesvirus; B cells; latency; lymphoma; carcinoma; leiomyosarcoma; autoimmune diseases; vaccine; sequence variation; micro‐RNAs

Figure 1. Electron micrograph of the Epstein–Barr virus (EBV) virion.
Figure 2. EBV primary infection and persistence. Figure showing putative in vivo interactions between EBV and host cells. (a) Primary infection. EBV replicates in epithelial cells and spreads to lymphoid tissues as a latent growth‐transforming (latency III) infection of B cells. Many infected B cells are removed by emerging EBV‐specific T‐cell response. Some infected cells escape by downregulating EBV latent genes to establish a stable pool of resting virus‐positive memory B cells. (b) Persistent infection. EBV‐infected memory B cells become subject to the physiological controls governing memory B‐cell migration and differentiation. Occasional recruitment into germinal centre (GC) reactions resulting in activation of different EBV latency programmes and reentry into the memory cell reservoir or plasma cell differentiation with activation of virus lytic cycle. Infectious virions then initiate foci of EBV replication in epithelial cells and also new growth‐transforming infection of naïve and/or memory B cells. For more detailed explanations, see Young and Rickinson and Thorley‐Lawson and Gross . Reproduced from Mahy and Van Regenmortel © Elsevier.
Figure 3. EBV genome forms. (a) The episome, in which the EBV genome circularises via the terminal repeats (TR), is the hallmark of EBV latency. EBNA1 is the principal EBV latency protein. EBNA promoters are shown (Cp, Wp, Qp), as well as the EBNA1 open reading frame (triangle). Shaded circles represent the two areas of the EBV genome where EBNA1 dimers bind. Two binding sites are found in the Q locus, whereas 24 binding sites are found within the plasmid origin of replication (ori‐P). EBNA‐1 activates ori‐P and autoregulates Qp. (b) The linear EBV genome is diagnostic of productive infection. The positions of terminal (TR) and internal direct (IR) repeat units are shown. Regions of unique sequence are designated U. Latent and lytic (ori‐lyt) origins of DNA (deoxyribonucleic acid) replication are shown as open circles. Arrows pointing rightward or leftward indicate the location and direction of transcription of the coding sequences of the EBV genes mentioned in the text.


Babcock GJ, Decker LL, Volk M and Thorley‐Lawson DA (1998) EBV persistence in memory B cells in vivo. Immunity 9: 395–404.

Baer R, Bankier AT, Biggin MD, et al. (1984) DNA sequence and expression of the B95‐8 Epstein–Barr virus genome. Nature 310 (5974): 207–211.

Ballard AJ (2015) Epstein–Barr virus infection is equally distributed across the invasive ductal and invasive lobular forms of breast cancer. Pathology, Research and Practice 211 (12): 1003–1005.

Burkitt D (1962) Determining the climatic limitations of a children's cancer common in Africa. British Medical Journal 2: 1019–1023.

Chan ATC, Lo YMD, Zee B, et al. (2002) Plasma Epstein–Barr virus DNA and residual disease after radiotherapy for undifferentiated nasopharyngeal carcinoma. Journal of the National Cancer Institute 94: 1614–1619.

Chan AT, Tão Q, Robertson KD, et al. (2004) Azacitidine induces demethylation of the Epstein–Barr virus genome in tumors. Journal of Clinical Oncology 22: 1373–1381.

Chen J, Jardetzky TS and Longnecker R (2016) The cytoplasmic tail domain of Epstein–Barr virus gH regulates membrane fusion activity through altering gH binding to gp42 and epithelial cell attachment. mBio 7 (6). DOI: 10.1128/mBio.01871-16.

Cohen JI (2015) Epstein–Barr virus vaccines. Clinical & Translational Immunology 4 (1): e32.

Countryman J and Miller G (1985) Activation of expression of latent Epstein–Barr herpesvirus after gene transfer with a small cloned subfragment of heterogeneous DNA. Proceedings of the National Academy of Sciences of the United States of America 82: 4085–4089.

Dalla‐Favera R, Bregni M, Erikson J, et al. (1982) Human c‐myc oncogene is located on the region of chromosome 8 that is translocated in Burkitt's lymphoma cells. Proceedings of the National Academy of Sciences of the United States of America 77: 2999–3003.

Epstein MA, Achong BG and Barr YM (1964) Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet 1 (7335): 702–703.

Fuentes‐Pananá EM, Larios‐Serrato V, Mendez‐Tenorio A, et al. (2016) Assessment of Epstein–Barr virus nucleic acids in gastric but not in breast cancer by next‐generation sequencing of pooled Mexican samples. Memórias do Instituto Oswaldo Cruz 111 (3): 200–208.

Gleeson M, Pyne DB, Austin JP, et al. (2002) Epstein–Barr virus reactivation and upper‐respiratory illness in elite swimmers. Medicine and Science in Sports and Exercise 34 (3): 411–417.

Gleeson M, Pyne DB, Elkington LJ, et al.et al. (2017) Developing a multi‐component immune model for evaluating the risk of respiratory illness in athletes. Exercise Immunology Review 23: 52–64.

Greenspan JS, Greenspan D, Lennette ET, et al. (1985) Replication of Epstein–Barr virus within the epithelial cells of oral “hairy” leukoplakia, an AIDS‐associated lesion. New England Journal of Medicine 313: 1564–1571.

zur Hausen H, Schulte‐Holthausen H, Klein G, et al. (1970) EBV DNA in biopsies of Burkitt tumors and anaplastic carcinomas of the nasopharynx. Nature 228: 1056–1058.

Henle G, Henle W and Diehl V (1968) Relation of Burkitt's tumor‐associated herpes‐type virus to infectious mononucleosis. Proceedings of the National Academy of Sciences of the United States of America 59: 94–101.

Hu H, Luo ML, Desmedt C, et al.et al. (2016) Epstein–Barr virus infection of mammary epithelial cells promotes malignant transformation. EBioMedicine 9: 148–160.

Israel BF and Kenney SC (2003) Virally targeted therapies for EBV‐associated malignancies. Oncogene 22: 5122–5130.

Jenkins PJ and Farrell PJ (1996) Are particular Epstein–Barr virus strains linked to disease? Seminars in Cancer Biology 7 (4): 209–215.

Kelly G, Bell A and Rickinson A (2002) Epstein–Barr virus‐associated Burkitt lymphomagenesis selects for downregulation of the nuclear antigen EBNA2. Nature Medicine 8: 1098–1104.

Kilger E, Kieser A, Baumann M and Hammerschmidt W (1998) Epstein–Barr virus‐mediated B‐cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor. EMBO Journal 17: 1700–1709.

Labrecque LG, Barnes DM, Fentiman IS and Griffin BE (1995) Epstein–Barr virus in epithelial cell tumors: a breast cancer study. Cancer Research 55 (1): 39–45.

Lee ES, Locker J, Nalesnik M, et al. (1995) The association of Epstein–Barr virus with smooth‐muscle tumors occurring after organ transplantation. The New England Journal of Medicine 332 (1): 19–25.

Levitskaya J, Sharipo A, Leonchiks A, Ciechanover A and Masucci MG (1997) Inhibition of ubiquitin/proteasome‐dependent protein degradation by the Gly Ala repeat domain of the Epstein–Barr virus nuclear antigen 1. Proceedings of the National Academy of Sciences of the United States of America 94: 12616–12621.

Ling PD, Rawlins DR and Hayward SD (1993) The Epstein–Barr virus immortalizing protein EBNA‐2 is targeted to DNA by a cellular enhancer‐binding protein. Proceedings of the National Academy of Sciences of the United States of America 90: 9237–9241.

Lo KW and Huang DP (2002) Genetic and epigenetic changes in nasopharyngeal carcinoma. Seminars in Cancer Biology 12: 451–462.

Longnecker R (2000) Epstein–Barr virus latency: LMP2, a regulator or means for Epstein–Barr virus persistence? Advances in Cancer Research 79: 175–200.

Mahy BWJ and Van Regenmortel MHV (2008) Epstein–Barr virus: General features. In: Encyclopedia of Virology. 3rd edn. Oxford, UK: Academic Press. ISBN: 978-0-12-374410-4

Mazouni C, Fina F, Romain S, et al. (2011) Epstein–Barr virus as a marker of biological aggressiveness in breast cancer. British Journal of Cancer 104 (2): 332–337.

McClain KL, Leach CT, Jenson HB, et al. (1995) Association of Epstein–Barr virus with leiomyosarcomas in young people with AIDS. The New England Journal of Medicine 332 (1): 12–18.

Morris MA, Dawson CW and Young LS (2009) Role of the Epstein–Barr virus‐encoded latent membrane protein‐1, LMP1, in the pathogenesis of nasopharyngeal carcinoma. Future Oncology (London, England) 5 (6): 811–825.

Morris MA, Dawson CW, Laverick L, et al. (2016) The Epstein–Barr virus encoded LMP1 oncoprotein modulates cell adhesion via regulation of activin A/TGFbeta and beta1 integrin signalling. Scientific Reports 6: 19533.

Mosialos G, Birkenbach M, Yalamanchili R, et al. (1995) The Epstein–Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80: 389–399.

Nawandar DM, Ohashi M, Djavadian R, et al. (2017) Differentiation‐dependent LMP1 expression is required for efficient lytic EBV reactivation in epithelial cells. Journal of Virology 91 (8). DOI: 10.1128/JVI.02438-16.

Pfeffer S, Zavolan M, Grasser F, et al. (2004) Identification of virus‐encoded microRNAS. Science 304: 734–736.

Raab‐Traub N and Flynn K (1986) The structure of the termini of the Epstein–Barr virus as a marker of clonal cellular proliferation. Cell 47: 883–889.

Rooney CM, Smith CA, Ng CY, et al. (1995) Use of gene‐modified virus‐specific T lymphocytes to control Epstein–Barr‐virus‐related lymphoproliferation. Lancet 345: 9–13.

Ruiss R, Jochum S, Wanner G, et al. (2011) A virus‐like particle‐based Epstein–Barr virus vaccine. Journal of Virology 85 (24): 13105–13113.

Santón A, Cristobal E, Aparicio M, et al. (2011) High frequency of co‐infection by Epstein–Barr virus types 1 and 2 in patients with multiple sclerosis. Multiple Sclerosis (Houndmills, Basingstoke, England) 17 (11): 1295–1300.

Seto E, Ooka T, Middeldorp J and Takada K (2008) Reconstitution of nasopharyngeal carcinoma‐type EBV infection induces tumorigenicity. Cancer Research 68: 1030–1036.

Skalsky RL (2017) Analysis of viral and cellular MicroRNAs in EBV‐infected cells. Methods in Molecular Biology (Clifton, NJ) 1532: 133–146.

Sokal EM, Hoppenbrouwers K, Vandermeulen C, et al. (2007) Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomised, double‐blind, placebo‐controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein–Barr virus vaccine in healthy young adults. Journal of Infectious Diseases 196: 1749–1753.

Tao C, Simpson S Jr, Taylor BV and van der Mei I (2017) Association between human herpesvirus & human endogenous retrovirus and MS onset & progression. Journal of the Neurological Sciences 372: 239–249.

Tetzlaff MT, Nosek C and Kovarik CL (2011) Epstein–Barr virus‐associated leiomyosarcoma with cutaneous involvement in an African child with human immunodeficiency virus: a case report and review of the literature. Journal of Cutaneous Pathology 38 (9): 731–739.

Thorley‐Lawson DA and Gross A (2004) Persistence of the Epstein–Barr virus and the origins of associated lymphomas. New England Journal of Medicine 350: 1328–1337.

Thorley‐Lawson DA and Allday MJ (2008) The curious case of the tumour virus: 50 years of Burkitt's lymphoma. Nature Reviews. Cancer 6: 913–924.

Tsai MH, Lin X, Shumilov A, et al. (2017) The biological properties of different Epstein–Barr virus strains explain their association with various types of cancers. Oncotarget 8 (6): 10238–10254.

Tzellos S and Farrell PJ (2012) Epstein‐Barr Virus Sequence Variation ‐ Biology and Disease. Pathogens 1 (2): 156–174.

Wang D, Liebowitz D and Kieff E (1985) An Epstein–Barr virus protein expressed in immortalized lymphocytes transforms established rodent cells. Cell 43: 831–840.

Yates J, Warren N and Sugden B (1985) Stable replication of plasmids derived from Epstein–Barr virus in various mammalian cells. Nature 313: 812–815.

Young L, Alfieri C, Hennessy K, et al. (1989) Expression of Epstein–Barr virus transformation‐associated genes in tissues of patients with EBV lymphoproliferative disease. New England Journal of Medicine 32: 1080–1085.

Young LS and Rickinson AB (2004) Epstein–Barr virus: 40 years on. Nature Reviews. Cancer 4: 757–768.

Further Reading

Kieff E and Rickinson AB (2006) Epstein–Barr virus and its replication. In: Knipe DM and Howley PM (eds) Fields Virology, 5th edn. Philadelphia, PA: Lippincott Williams and Wilkins Publishers.

Kuppers R (2005) Mechanisms of B cell lymphoma pathogenesis. Nature Reviews. Cancer 5: 251–262.

Kutok JL and Wang F (2006) Spectrum of Epstein–Barr virus‐associated diseases. Annual Review of Pathology: Mechanisms of Disease 1: 375–404.

Rickinson AB and Kieff E (2006) Epstein–Barr virus. In: Knipe DM and Howley PM (eds) Fields Virology, 5th edn. Philadelphia, PA: Lippincott Williams and Wilkins Publishers.

Robertson ES (ed) (2005) Epstein–Barr Virus. Norfolk, UK: Caister Academic Press.

Tao Q, Young LS, Woodman CB and Murray PG (2006) Epstein–Barr virus and its associated cancers – genetics, epigenetics, pathobiology and novel therapeutics. Frontiers in Bioscience 11: 2672–2713.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Morris, Mhairi A(Jun 2017) Epstein–Barr Virus. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001020.pub3]