Epstein–Barr virus infection: from infectious mononucleosis to lymphoproliferative disorder


DOI: https://dx.doi.org/10.18565/therapy.2021.2.112-122

Mazus A.I., Tsyganova E.V., Glukhoedova N.V., Zhilenkova A.S.

Moscow City Center for the Prevention and Control of AIDS of Moscow Healthcare Department
Abstract. Epstein–Barr virus (EBV), as a member of the herpesvirus family, successfully and permanently persists in the human body after contamination. Due to its complicated life cycle and complex interaction with various components of innate and adaptive immunity, EBV is able to use the programs of cell death and inflammation for its own properties. Currently, the proliferative potential of EBV has been described and studied; besides latent infection, it can cause the development of such rare diseases as chronic active EBV infection and a number of virus-induced neoplasms. The review summarizes information about EBV infection, considers the studied moments of interaction within virus–macroorganism system, and provides clinical parallels. Definitely, the subject needs further comprehensive study, and authors of the article, without pretending to the finality of viewpoints, only want to reveal the scale of the problem for a wide range of medical specialists.
Keywords: Epstein–Barr virus, infectious mononucleosis, chronic active Epstein–Barr viral infection
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Literature


  1. Jangra S., Yuen K.S., Botelho M.G., Jin DY. Epstein–Barr virus and innate immunity: Friends or foes? Microorganisms. 2019; 7(6): 183. doi: 10.3390/microorganisms7060183.

  2. Kuri A., Jacobs B.M., Vickaryous N. et al. Epidemiology of Epstein–Barr virus infection and infectious mononucleosis in the United Kingdom. BMC Public Health. 2020; 20(1): 912. doi: 10.1186/s12889-020-09049-x.

  3. Luzuriaga K., Sullivan J.L. Infectious mononucleosis. N Engl J Med. 2010; 362(21): 1993–2000. doi: 10.1056/NEJMcp1001116.

  4. Balfour H.H. Jr, Sifakis F., Sliman J.A. et al. Age-Specific prevalence of Epstein–Barr virus infection among individuals aged 6–19 years in the United States and factors affecting its acquisition. J Infect Dis. 2013; 208(8): 1286–93. doi: 10.1093/infdis/jit321.

  5. Dowd J.B., Palermo T., Brite J. et al. Seroprevalence of Epstein–Barr virus infection in U.S. children ages 6–19, 2003–2010. PLoS One. 2013; 8(5): e64921. doi: 10.1371/journal.pone.0064921.

  6. Balfour H.H., Dunmire S.K., Hogquist K.A. Infectious mononucleosis. Clin Transl Immunology. 2015; 4(2): e33. doi: 10.1038/cti.2015.1.

  7. Kanda T., Yajima M., Ikuta K. Epstein–Barr virus strain variation and cancer. Cancer Sci. 2019; 110(4): 1132–39. doi: 10.1111/cas.13954.

  8. AbuSalah M.A.H., Gan S.H., Al-Hatamleh M.A.I. et al. Recent advances in diagnostic approaches for Epstein–Barr virus. Pathogens. 2020; 9(3): 226. doi: 10.3390/pathogens9030226.

  9. Lunemann J.D., Kamradt T., Martin R., Munz C. Epstein–Barr virus: environmental trigger of multiple sclerosis? J Virol. 2007; 81(13): 6777–84. doi: 10.1128/JVI.00153-07.

  10. Pender M.P. Epstein–Barr virus and autoimmunity. Infect Autoimmun. 2nd ed. 2004: 163–70. doi: 10.1016/B978-044451271-0/50013-2.

  11. Fujiwara S., Takei M. Epstein–Barr virus and autoimmune diseases. Clin Exp Neuroimmunol. 2015; 6(S1): 38–48. doi: 10.1111/cen3.12263.

  12. Xu T., Zhao Q., Li W. et al. X-linked lymphoproliferative syndrome in mainland China: review of clinical, genetic, and immunological characteristic. Eur J Pediatr. 2020; 179(2): 327–38. doi: 10.1007/s00431-019-03512-7.

  13. Panchal N., Booth C., Cannons J.L., Schwartzberg P.L. X-linked lymphoproliferative disease type 1: A clinical and molecular perspective. Front Immunol. 2018; 9: 666. doi: 10.3389/fimmu.2018.00666.

  14. Blackburn P.R., Lin W.L., Miller D.A. et al. X-linked lymphoproliferative syndrome presenting as adult-onset multi-infarct dementia. J Neuropathol Exp Neurol. 2019; 78(5): 460–66. doi: 10.1093/jnen/nlz018.

  15. Gulley M.L., Tang W. Laboratory assays for Epstein–Barr virus-related disease. J Mol Diagn. 2008; 10(4): 279–92. doi: 10.2353/jmoldx.2008.080023.

  16. Stanland L.J., Luftig M.A. The role of EBV-induced hypermethylation in gastric cancer tumorigenesis. Viruses. 2020; 12(11): 1222. doi: 10.3390/v12111222.

  17. Chang M.S., Kim H., Kim W.H. Epstein–Barr virus in human malignancy: A Special Reference to Epstein–Barr virus associated gastric carcinoma. Cancer Res Treat. 2005; 37(5): 257–67. doi: 10.4143/crt.2005.37.5.257.

  18. Shannon-Lowe C., Rickinson A.B., Bell A.I. Epstein–Barr virus-associated lymphomas. Philos Trans R Soc Lond B Biol Sci. 2017; 372(1732): 20160271. doi: 10.1098/rstb.2016.0271.

  19. Huppmann A.R., Nicolae A., Slack G.W. et al. EBV may be expressed in the LP cells of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) in both children and adults. Am J Surg Pathol. 2014; 38(3): 316–24. doi: 10.1097/PAS.0000000000000107.

  20. Carbone A., Gloghini A. Epstein Barr virus-associated Hodgkin lymphoma. Cancers (Basel). 2018; 10(6): 163. doi: 10.3390/cancers10060163.

  21. Chang C.M., Yu K.J., Mbulaiteye S.M., Hildesheim A, Bhatia K. The extent of genetic diversity of Epstein-Barr virus and its geographic and disease patterns: A need for reappraisal. Virus Res. 2009; 143(2): 209–21. doi: 10.1016/j.virusres.2009.07.005.

  22. Kwok H., Chiang A.K.S. From conventional to next generation sequencing of Epstein–Barr virus genomes. Viruses. 2016; 8(3): 60. doi: 10.3390/v8030060.

  23. Tzellos S., Farrell P.J. Epstein–Barr virus sequence variation-biology and disease. Pathogens. 2012; 1(2): 156–74. doi: 10.3390/pathogens1020156.

  24. Johnston W.T., Mutalima N., Sun D. et al. Relationship between Plasmodium falciparum malaria prevalence, genetic diversity and endemic Burkitt lymphoma in Malawi. Sci Rep. 2014; 4: 3741. doi: 10.1038/srep03741.

  25. Mahdavifar N., Ghoncheh M., Mohammadian-Hafshejani A. et al. Epidemiology and inequality in the incidence and mortality of nasopharynx cancer in Asia. Osong Public Health Res Perspect. 2016; 7(6): 360–72. doi: 10.1016/j.phrp.2016.11.002.

  26. Cohen J.I., Fauci A.S., Varmus H., Nabel G.J. Epstein–Barr virus: An important vaccine target for cancer prevention. Sci Transl Med. 2011; 3(107): 107fs7. doi: 10.1126/scitranslmed.3002878.

  27. Hildesheim A., Wang C.P. Genetic predisposition factors and nasopharyngeal carcinoma risk: A review of epidemiological association studies, 2000–2011: Rosetta Stone for NPC: genetics, viral infection, and other environmental factors. Semin Cancer Biol. 2012; 22(2): 107–16. doi: 10.1016/j.semcancer.2012.01.007.

  28. Kimura H., Ito Y., Kawabe S. et al. EBV-associated T/NK-cell lymphoproliferative diseases in nonimmunocompromised hosts: Prospective analysis of 108 cases. Blood. 2012; 119(3): 673–86. doi: 10.1182/blood-2011-10-381921.

  29. Buschle A., Hammerschmidt W. Epigenetic lifestyle of Epstein–Barr virus. Semin Immunopathol. 2020; 42(2): 131–42. doi: 10.1007/s00281-020-00792-2.

  30. Jochum S., Ruiss R., Moosmann A. et al. RNAs in Epstein-Barr virions control early steps of infection. Proc Natl Acad Sci U S A. 2012; 109(21): E1396–404. doi: 10.1073/pnas.1115906109.

  31. Mrozek-Gorska P., Buschle A., Pich D. et al. Epstein-Barr virus reprograms human B lymphocytes immediately in the prelatent phase of infection. Proc Natl Acad Sci U S A. 2019; 116(32): 16046–55. doi: 10.1073/pnas.1901314116.

  32. Amon W., Binne U.K., Bryant H. et al. Lytic cycle gene regulation of Epstein–Barr virus. J Virol. 2004; 78(24): 13460–69. doi: 10.1128/JVI.78.24.13460-13469.2004.

  33. Ersing I., Nobre L., Wang L.W. et al. A temporal proteomic map of Epstein–Barr virus lytic replication in B cells. Cell Rep. 2017; 19(7): 1479–93. doi: 10.1016/j.celrep.2017.04.062.

  34. Lupey-Green L.N., Moquin S.A., Martin K.A. et al. PARP1 restricts Epstein Barr virus lytic reactivation by binding the BZLF1 promoter. Virology. 2017; 507: 220–30. doi: 10.1016/j.virol.2017.04.006.

  35. Odumade O.A., Hogquist K.A., Balfour H.H. Progress and problems in understanding and managing primary Epstein–Barr virus infections. Clin Microbiol Rev. 2011; 24(1): 193–209. doi: 10.1128/CMR.00044-10.

  36. Wingate P.J., McAulay K.A., Anthony I.C., Crawford D.H. Regulatory T cell activity in primary and persistent Epstein–Barr virus infection. J Med Virol. 2009; 81(5): 870–77. doi: 10.1002/jmv.21445.

  37. Lanier L.L. Evolutionary struggles between NK cells and viruses. Nat Rev Immunol. 2008; 8(4): 259–68. doi: 10.1038/nri2276.

  38. Orange J.S. Human natural killer cell deficiencies and susceptibility to infection. Microbes Infect. 2002; 4(15): 1545–58. doi: 10.1016/s1286-4579(02)00038-2.

  39. Zhang Y., Wallace D.L., de Lara C.M. et al. In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection. Immunology. 2007; 121(2): 258–65. doi: 10.1111/j.1365-2567.2007.02573.x.

  40. Silins S.L., Sherritt M.A., Silleri J.M. et al. Asymptomatic primary Epstein-Barr virus infection occurs in the absence of blood T-cell repertoire perturbations despite high levels of systemic viral load. Blood. 2001; 98(13): 3739–44. doi: 10.1182/blood.v98.13.3739.

  41. Long H.M., Chagoury O.L., Leese A.M. et al. 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. 2013; 210(5): 933–49. doi: 10.1084/jem.20121437.

  42. Hess R.D. Routine Epstein–Barr virus diagnostics from the laboratory perspective: Still challenging after 35 years. J Clin Microbiol. 2004; 42(8): 3381–87. doi: 10.1128/JCM.42.8.3381-3387.2004.

  43. Nystad T.W., Myrmel H. Prevalence of primary versus reactivated Epstein–Barr virus infection in patients with VCA IgG-, VCA IgM- and EBNA-1-antibodies and suspected infectious mononucleosis. J Clin Virol. 2007; 38(4): 292–97. doi: 10.1016/j.jcv.2007.01.006.

  44. Teow S.Y., Liew K., Khoo A.S., Peh S.C. Pathogenic role of exosomes in Epstein–Barr virus (EBV)-associated cancers. Int J Biol Sci. 2017; 13(10): 1276–86. doi: 10.7150/ijbs.19531.

  45. Teow S.Y., Peh S.C. Exosomes as the promising biomarker for Epstein–Barr virus (EBV)-associated cancers. Novel Implications of Exosomes in Diagnosis and Treatment of Cancer and Infectious Diseases. Ed. by Wang J. InTechOpen. 2017: 97–114. doi: 10.5772/intechopen.69532.

  46. Wu Y., Ma S., Zhang L. et al. Clinical manifestations and laboratory results of 61 children with infectious mononucleosis. J Int Med Res. 2020; 48(10): 300060520924550. doi: 10.1177/0300060520924550.

  47. Ciccarese G., Trave I., Herzum A. et al. Dermatological manifestations of Epstein–Barr virus systemic infection: a case report and literature review. Int J Dermatol. 2020; 59(10): 1202–09. doi: 10.1111/ijd.14887.

  48. Chuh A., Zawar V., Law M., Sciallis G. Gianotti–Crosti syndrome, pityriasis rosea, asymmetrical periflexural exanthem, unilateral mediothoracic exanthem, eruptive pseudoangiomatosis, and papular-purpuric gloves and socks syndrome: a brief review and arguments for diagnostic criteria. Infect Dis Rep. 2012; 4(1): e12. doi: 10.4081/idr.2012.e12.

  49. Womack J., Jimenez M. Common questions about infectious mononucleosis. Am Fam Physician. 2015; 91(6): 372–76.

  50. Dunmire S.K., Verghese P.S., Balfour H.H. Primary Epstein–Barr virus infection. J Clin Virol. 2018; 102: 84–92. doi: 10.1016/j.jcv.2018.03.001.

  51. Fugl A., Andersen C.L. Epstein–Barr virus and its association with disease – A review of relevance to general practice. BMC Fam Pract. 2019; 20(1): 62. doi: 10.1186/s12875-019-0954-3.

  52. De Paor M., O’Brien K., Fahey T., Smith S.M. Antiviral agents for infectious mononucleosis (glandular fever). Cochrane Database Syst Rev. 2016; 12(12): CD011487. doi: 10.1002/14651858.CD011487.pub2.

  53. Lennon P., O’Neill J.P., Fenton J.E. Effect of metronidazole versus standard care on length of stay of patients admitted with severe infectious mononucleosis: A randomized controlled trial. Clin Microbiol Infect. 2014; 20(7): O450–52. doi: 10.1111/1469-0691.12437.

  54. Lennon P., Crotty M., Fenton J.E. Infectious mononucleosis. BMJ. 2015; 350: h1825. doi: 10.1136/bmj.h1825.

  55. Rezk E., Nofal Y.H., Hamzeh A. et al. Steroids for symptom control in infectious mononucleosis. Cochrane Database Syst Rev. 2015; 2015(11): CD004402. doi: 10.1002/14651858.CD004402.pub3.

  56. Arai A. Advances in the study of chronic active Epstein–Barr virus infection: Clinical features under the 2016 WHO classification and mechanisms of development. Front Pediatr. 2019; 7: 14. doi: 10.3389/fped.2019.00014.

  57. Okano M., Kawa K., Kimura H. et al. Proposed guidelines for diagnosing chronic active Epstein–Barr virus infection. Am J Hematol. 2005; 80(1): 64–69. doi: 10.1002/ajh.20398.


About the Autors

Alexey I. Mazus, MD, professor, chief external expert on HIV infection of the Russian Ministry of Healthcare and Moscow City Healthcare Department, head of the Moscow City Center for the Prevention and Control of AIDS of Moscow Healthcare Department. Address: 105275, Moscow, 15/5 8ya Ulitza Sokolinoy Gory Str. Tel.: +7 (495) 365-21-52. E-mail: aids@spid.ru. ORCID: 0000-0003-2581-1443
Elena V. Tsyganova, PhD, infectious disease physician, head of the scientific and clinical Department of the Moscow City Center for the Prevention and Control of AIDS of Moscow Healthcare Department. Address: 105275, Moscow, 15/5 8ya Ulitsa Sokolinoy Gory Str. Tel.: +7 (916) 846-88-29. E-mail: TsyganovaElena@yandex.ru. ORCID: 0000-0002-3410-2510
Natalia V. Glukhoedova, PhD, infectious disease physician of the scientific and clinical Department of the Moscow City Center for the Prevention and Control of AIDS of Moscow Healthcare Department. Address: 105275, Moscow, 15/5 8ya Ulitsa Sokolinoy Gory Str. Tel.: +7 (926) 121-18-18. E-mail: febris1@yandex.ru. ORCID: 0000-0003-2414-6103
Alexandra S. Zhilenkova, infectious disease physician of the scientific and clinical department of the Moscow City Center for the Prevention and Control of AIDS of Moscow Healthcare Department. Address: 105275, Moscow, 15/5 8ya Ulitsa Sokolinoy Gory Str. Tel.: +7 (915) 178-74-37. E-mail: o.zhilenkova@mail.ru. ORCID: 0000-0001-8139-4061

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