View source for Epstein–Barr virus

{{Short description|Virus of the herpes family}}
{{Redirect|EBV}}
{{Cs1 config|name-list-style=vanc|display-authors=6}}
{{Use dmy dates |date=September 2020}}
{{Use American English|date=September 2024}}
{{Virusbox
| image = Epstein Barr Virus virions EM 10.1371 journal.pbio.0030430.g001-L.JPG
| image_alt = Electron microscopic image of two Epstein–Barr virus virions (viral particles) showing round capsids (protein-encased genetic material) loosely surrounded by the membrane envelope
| image_caption = [[Electron micrograph]] of two Epstein–Barr virions (viral particles) showing round [[capsid]]s loosely surrounded by the membrane [[Viral envelope|envelope]]
| parent = Lymphocryptovirus
| species = Human gammaherpesvirus 4
| synonyms =
* ''Epstein–Barr virus''
* ''Human herpesvirus 4''
* ''HHV-4''
* ''EBV''
| synonyms_ref = <ref>{{cite web |title=ICTV Taxonomy history: ''Human gammaherpesvirus&nbsp;4'' |website=International Committee on Taxonomy of Viruses (ICTV) |url=https://ictv.global/taxonomy/taxondetails?taxnode_id=20181486 |access-date=10 January 2019 |archive-date=16 August 2022 |archive-url=https://web.archive.org/web/20220816070311/https://ictv.global/taxonomy/taxondetails?taxnode_id=20181486 |url-status=live }}</ref>
}}
The '''Epstein–Barr virus''' ('''EBV'''), formally called '''''Human gammaherpesvirus&nbsp;4''''', is one of the nine known [[Herpesviridae#Human herpesvirus types|human herpesvirus types]] in the [[Herpesviridae|herpes family]], and is one of the most common [[virus]]es in humans. EBV is a [[DNA virus#Double-stranded DNA viruses|double-stranded DNA virus]].<ref name=pmid-32847820>{{cite journal | vauthors=Zanella M, Cordey S, Kaiser L | year=2020 | title=Beyond cytomegalovirus and Epstein–Barr virus: A review of viruses composing the blood virome of solid organ transplant and hematopoietic stem cell transplant recipients | journal=[[Clinical Microbiology Reviews]] | volume=33 | issue=4 | page=e00027-20 | doi = 10.1128/CMR.00027-20 | pmc=7462738 | pmid=32847820}}</ref> Epstein–Barr virus (EBV) is the first identified [[oncogenic virus]], or a virus that can cause [[cancer]]. EBV establishes permanent infection in humans. It causes [[infectious mononucleosis]] and is also tightly linked to many [[Malignancy|malignant]] diseases (cancers). Various [[vaccine]] formulations underwent testing in different animals or in humans. However, none of them were able to prevent EBV infection and no vaccine has been approved to date.<ref>Urgency and necessity of Epstein–Barr virus prophylactic vaccines. 2022. npj Vaccines. 7/1. L. Zhong, C. Krummenacher, W. Zhang, J. Hong, Q. Feng, Y. Chen, et al. doi: 10.1038/s41541-022-00587-6.</ref>
[[Infectious mononucleosis]] ("mono" or "glandular fever"), a disease caused by the virus, is characterized by extreme fatigue, fever, sore throat, and swollen lymph nodes. The virus is also associated with various non-malignant, [[premalignant]], and malignant [[Epstein–Barr virus-associated lymphoproliferative diseases]] such as [[Burkitt lymphoma]], [[hemophagocytic lymphohistiocytosis]],<ref name=pmid-29885408>{{cite journal | vauthors = Rezk SA, Zhao X, Weiss LM | date = September 2018 | title = Epstein–Barr virus (EBV)-associated lymphoid proliferations, a 2018 update | journal = [[Human Pathology]] | volume = 79 | pages = 18–41 | pmid = 29885408 | doi = 10.1016/j.humpath.2018.05.020 | s2cid = 47010934 }}</ref> and [[Hodgkin lymphoma|Hodgkin's lymphoma]]; non-lymphoid malignancies such as [[gastric cancer]] and [[nasopharyngeal carcinoma]]; and conditions associated with [[human immunodeficiency virus]] such as [[hairy leukoplakia]] and [[central nervous system]] [[lymphoma]]s.<ref name=pmid-19373526>{{cite journal | vauthors = Maeda E, Akahane M, Kiryu S, Kato N, Yoshikawa T, Hayashi N, Aoki S, Minami M, Uozaki H, Fukayama M, Ohtomo K | date = January 2009 | title = Spectrum of Epstein–Barr virus-related diseases: A pictorial review | journal = [[Japanese Journal of Radiology]] | volume = 27 | issue = 1 | pages = 4–19 | pmid = 19373526 | doi = 10.1007/s11604-008-0291-2 | s2cid = 6970917 }}</ref><ref>{{cite journal | vauthors = Cherry-Peppers G, Daniels CO, Meeks V, Sanders CF, Reznik D | date = February 2003 | title = Oral manifestations in the era of HAART | journal = [[Journal of the National Medical Association]] | volume = 95 | issue = 2, Supplement&nbsp;2 | pages = 21S–32S | pmid = 12656429 | pmc = 2568277 }}</ref> The virus is also associated with the childhood disorders of [[Alice in Wonderland syndrome]]<ref name=pmid-28116304>{{cite journal | vauthors = Mastria G, Mancini V, Viganò A, di Piero V | year = 2016 | title = Alice in Wonderland Syndrome: A clinical and pathophysiological review | journal = [[BioMed Research International]] | volume = 2016 | page = 8243145 | pmid = 28116304 | pmc = 5223006 | doi = 10.1155/2016/8243145 | doi-access = free }}</ref> and [[acute cerebellar ataxia of childhood|acute cerebellar ataxia]]<ref name=pmid-14552515>{{cite journal | vauthors = Nussinovitch M, Prais D, Volovitz B, Shapiro R, Amir J | date = September 2003 | title = Post-infectious acute cerebellar ataxia in children | journal = [[Clinical Pediatrics]] | volume = 42 | issue = 7 | pages = 581–584 | pmid = 14552515 | doi = 10.1177/000992280304200702 | s2cid = 22942874 }}</ref> and, by some evidence, higher risks of developing certain [[autoimmune disease]]s,<ref name=pmid-19028369>{{cite journal | vauthors = Toussirot E, Roudier J | date = October 2008 | title = Epstein–Barr virus in autoimmune diseases | journal = [[Best Practice & Research: Clinical Rheumatology]] | volume = 22 | issue = 5 | pages = 883–896 | pmid = 19028369 | doi = 10.1016/j.berh.2008.09.007 }}</ref> especially [[dermatomyositis]], [[systemic lupus erythematosus]], [[rheumatoid arthritis]], and [[Sjögren's syndrome]].<ref name=pmid-21871974>{{cite journal | vauthors = Dreyfus DH | title = Autoimmune disease: A role for new anti-viral therapies? | journal = [[Autoimmunity Reviews]] | volume = 11 | issue = 2 | pages = 88–97 | date = December 2011 | pmid = 21871974 | doi = 10.1016/j.autrev.2011.08.005 }}</ref><ref name=pmid-22312480>{{cite journal | vauthors = Pender MP | year = 2012 | title = CD8+ T&nbsp;cell deficiency, Epstein–Barr virus infection, vitamin&nbsp;D deficiency, and steps to autoimmunity: A unifying hypothesis | journal = [[Autoimmune Diseases (journal)|Autoimmune Diseases]] | volume = 2012 | page = 189096 | pmid = 22312480 | pmc = 3270541 | doi = 10.1155/2012/189096 | doi-access = free }}</ref> About 200,000 cancer cases globally per year are thought to be attributable to EBV.<ref name=Cancer-Research-UK-200000/><ref name=":0">{{cite journal | vauthors = Khan G, Fitzmaurice C, Naghavi M, Ahmed LA | date = August 2020 | title = Global and regional incidence, mortality and disability-adjusted life-years for Epstein–Barr virus-attributable malignancies, 1990–2017 | journal = [[BMJ Open]] | volume = 10 | issue = 8 | page = e037505 | pmid = 32868361 | pmc = 7462312 | doi = 10.1136/bmjopen-2020-037505 }}</ref> In 2022, a large study (population of 10 million over 20 years) suggested EBV as the leading cause of [[multiple sclerosis]], with a recent EBV infection causing a {{nowrap|32-fold}} increase in the risk of developing multiple sclerosis.<ref>{{cite journal | vauthors = Robinson WH, Steinman L | date = January 2022 | title = Epstein–Barr virus and multiple sclerosis | language = EN | journal = [[Science (journal)|Science]] | volume = 375 | issue = 6578 | pages = 264–265 | pmid = 35025606 | doi = 10.1126/science.abm7930 | s2cid = 245978874 | bibcode = 2022Sci...375..264R | doi-access = free }}</ref><ref name=pmid-35025605>{{cite journal | vauthors = Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, Elledge SJ, Niebuhr DW, Scher AI, Munger KL, Ascherio A | date = January 2022 | title = Longitudinal analysis reveals high prevalence of Epstein–Barr virus associated with multiple sclerosis | journal = [[Science (journal)|Science]] | volume = 375 | issue = 6578 | pages = 296–301 | pmid = 35025605 | doi = 10.1126/science.abj8222 | publisher = American Association for the Advancement of Science (AAAS) | bibcode = 2022Sci...375..296B | s2cid = 245983763 | doi-access =  }} Related non-technical article: {{Cite news |title=Can we vaccinate against Epstein–Barr, the virus you didn't know you had? |vauthors=Cox D |newspaper=The Observer |date=20 March 2022 |url=https://www.theguardian.com/science/2022/mar/20/can-we-vaccinate-against-epstein-barr-virus-multiple-sclerosis-cancer |access-date=20 March 2022 |archive-date=2 December 2022 |archive-url=https://web.archive.org/web/20221202035217/https://www.theguardian.com/science/2022/mar/20/can-we-vaccinate-against-epstein-barr-virus-multiple-sclerosis-cancer |url-status=live }}</ref><ref name=pmid-20369303>{{cite journal | vauthors = Ascherio A, Munger KL | date = September 2010 | title = Epstein-barr virus infection and multiple sclerosis: a review | journal = [[Journal of Neuroimmune Pharmacology]] | volume = 5 | issue = 3 | pages = 271–277 | pmid = 20369303 | doi = 10.1007/s11481-010-9201-3 | s2cid = 24409610 }}</ref><ref name=pmid-29892607/><ref>{{cite journal | vauthors = Hassani A, Corboy JR, Al-Salam S, Khan G | year = 2018 | title = Epstein–Barr virus is present in the brain of most cases of multiple sclerosis and may engage more than just B&nbsp;cells | journal = [[PLoS One]] | volume = 13 | issue = 2 | page = e0192109 | pmid = 29394264 | pmc = 5796799 | doi = 10.1371/journal.pone.0192109 | bibcode = 2018PLoSO..1392109H | doi-access = free }}</ref>
Infection with EBV occurs by the oral transfer of [[saliva]]<ref name=pmid-15546128>{{cite journal | vauthors = Amon W, Farrell PJ | date = November 2004 | title = Reactivation of Epstein–Barr virus from latency | journal = [[Reviews in Medical Virology]] | volume = 15 | issue = 3 | pages = 149–156 | pmid = 15546128 | doi = 10.1002/rmv.456 | s2cid = 19433994 }}</ref> and genital secretions. Most people become infected with EBV and gain [[adaptive immunity]]. In the United States, about half of all five-year-old children and about 90% of adults have evidence of previous infection.<ref name="CDC–2020-09-28-mono">{{Cite web |title=About 90% of adults have antibodies that show that they have a current or past EBV infection |date=28 September 2020 |publisher=US [[Centers for Disease Control|CDC]] |series=[[National Center for Infectious Diseases]] |url=https://www.cdc.gov/epstein-barr/about-ebv.html |url-status=live |archive-url=https://web.archive.org/web/20160808045418/http://www.cdc.gov/epstein-barr/about-ebv.htm |archive-date=2016-08-08}}</ref> Infants become susceptible to EBV as soon as [[Passive immunity#Naturally acquired|maternal antibody protection]] disappears. Many children who become infected with EBV display no symptoms or the symptoms are indistinguishable from the other mild, brief illnesses of childhood.<ref>{{cite journal | vauthors = Straus SE, Cohen JI, Tosato G, Meier J | date = January 1993 | title = NIH conference. Epstein–Barr virus infections: Biology, pathogenesis, and management | journal = [[Annals of Internal Medicine]] | volume = 118 | issue = 1 | pages = 45–58 | pmid = 8380053 | doi = 10.7326/0003-4819-118-1-199301010-00009 | s2cid = 53090545 }}</ref> When infection occurs during adolescence or young adulthood, it causes infectious mononucleosis 35 to 50% of the time.<ref>{{cite web |publisher = U.S. Centers for Disease Control and Prevention (CDC) |title=Epstein–Barr virus and infectious Mononucleosis |url=https://www.cdc.gov/ncidod/diseases/ebv.htm |access-date=2011-12-29 |url-status=dead |archive-url=https://web.archive.org/web/20120420113839/http://www.cdc.gov/ncidod/diseases/ebv.htm |archive-date=2012-04-20}}</ref>
EBV infects {{nobr|[[B cell]]s}} of the immune system and [[epithelial cells]]. Once EBV's initial [[lytic]] infection is brought under control, EBV [[virus latency|latency]] persists in the individual's {{nobr|[[memory B cell]]s}} for the rest of their life.<ref name=pmid-15546128/><ref>{{cite journal | vauthors = Khan G, Miyashita EM, Yang B, Babcock GJ, Thorley-Lawson DA | date = August 1996 | title = Is EBV persistence in vivo a model for B&nbsp;cell homeostasis? | journal = [[Immunity (journal)|Immunity]] | volume = 5 | issue = 2 | pages = 173–179 | pmid = 8769480 | doi = 10.1016/s1074-7613(00)80493-8 | doi-access = free }}</ref><ref name=pmid-34239514/>
==Virology==
[[File:Viral Tegument.svg|thumb|right|300px|Simplified diagram of the structure of EBV]]
===Structure and genome===
The [[virion|virus]] is about 122–180&nbsp;[[Nanometer|nm]] in diameter and is composed of [[Nucleic acid double helix|a double helix]] of [[deoxyribonucleic acid]] (DNA) which contains about 172,000&nbsp;[[base pairs]] encoding 85&nbsp;[[gene]]s.<ref name=pmid-15546128/> The DNA is surrounded by a protein [[nucleocapsid]], which is surrounded by a [[viral tegument|tegument]] made of protein, which in turn is surrounded by an  [[viral envelope|envelope]] containing both [[lipids]] and surface projections of [[glycoproteins]], which are essential to [[#Entry to the cell|infection of the host cell]].<ref name=pmid-21233512>{{cite journal | vauthors = Odumade OA, Hogquist KA, Balfour HH | date = January 2011 | title = Progress and problems in understanding and managing primary Epstein–Barr virus infections | journal = [[Clinical Microbiology Reviews]] | volume = 24 | issue = 1 | pages = 193–209 | pmid = 21233512 | pmc = 3021204 | doi = 10.1128/CMR.00044-10}}</ref> In July&nbsp;2020, a team of researchers reported the first complete atomic model of the nucleocapsid of the virus. This "first complete atomic model [includes] the icosahedral capsid, the capsid-associated tegument complex (CATC) and the dodecameric portal—the viral genome translocation apparatus."<ref>{{cite press release |vauthors=Jia L |date=July 17, 2020 |title=Scientists uncover first atomic structure of Epstein–Barr virus nucleocapsid |website=phys.org |url=https://phys.org/news/2020-07-scientists-uncover-atomic-epstein-bar-virus.html |access-date=October 4, 2020 |archive-date=18 July 2022 |archive-url=https://web.archive.org/web/20220718092223/https://phys.org/news/2020-07-scientists-uncover-atomic-epstein-bar-virus.html |url-status=live }}</ref><ref>{{cite journal | vauthors = Li Z, Zhang X, Dong L, Pang J, Xu M, Zhong Q, Zeng MS, Yu X | date = October 2020 | title = CryoEM structure of the tegumented capsid of Epstein–Barr virus | journal = [[Cell Research]] | volume = 30 | issue = 10 | pages = 873–884 | pmid = 32620850 | pmc = 7608217 | doi = 10.1038/s41422-020-0363-0 | s2cid = 220309464 | doi-access = free }}</ref>
===Tropism===
The term [[viral tropism]] refers to which cell types that EBV infects. EBV can infect different cell types, including {{nobr|[[B cell]]s}} and [[epithelial cells]].<ref>{{cite journal | vauthors = Shannon-Lowe C, Rowe M | date = February 2014 | title = Epstein Barr virus entry; kissing and conjugation | journal = [[Current Opinion in Virology]] | volume = 4 | pages = 78–84 | pmid = 24553068 | doi = 10.1016/j.coviro.2013.12.001 | doi-access = free }}</ref>
The viral three-part glycoprotein complexes of {{nobr|[[gHgL gp42]]}} mediate B&nbsp;cell membrane fusion; although the two-part complexes of gHgL mediate epithelial cell membrane fusion. EBV that are made in the B&nbsp;cells have low numbers of gHgLgp42 complexes, because these three-part complexes interact with [[Human leukocyte antigen|Human-leukocyte-antigen]] [[MHC Class II|class&nbsp;II]] molecules present in B&nbsp;cells in the endoplasmic reticulum and are degraded. In contrast, EBV from epithelial cells are rich in the three-part complexes because these cells do not normally contain {{nobr|HLA class II}} molecules. As a consequence, EBV made from B&nbsp;cells are more infectious to epithelial cells, and EBV made from epithelial cells are more infectious to B&nbsp;cells.  Viruses lacking the [[gp42]] portion are able to bind to human B&nbsp;cells, but unable to infect.<ref>{{cite journal | vauthors = Wang X, Hutt-Fletcher LM | date = January 1998 | title = Epstein–Barr virus lacking glycoprotein gp42 can bind to B&nbsp;cells but is not able to infect | journal = [[Journal of Virology]] | volume = 72 | issue = 1 | pages = 158–163 | pmid = 9420211 | pmc = 109360 | doi = 10.1128/jvi.72.1.158-163.1998 }}</ref>
===Replication cycle===
[[File:EBV infection cycle in healthy humans.png|thumb|350px|The EBV replication cycle]]
====Entry to the cell====
EBV can infect both B&nbsp;cells and epithelial cells. The mechanisms for entering these two cells are different.
To enter B&nbsp;cells, viral [[glycoprotein]] [[gp350]] binds to cellular receptor [[CD21]] (also known as CR2).<ref name=Entrez-CR2>{{cite web |title = Entrez gene: CR2 complement component (3d/Epstein Barr virus) receptor&nbsp;2 |website=ncbi.nlm.nih.gov |url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=1380 |url-status = live |archive-url = https://web.archive.org/web/20101205081110/http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene |archive-date = 2010-12-05}}</ref> Then, viral glycoprotein gp42 interacts with cellular [[MHC class II]] molecules. This triggers [[lipid bilayer fusion|fusion]] of the viral envelope with the cell membrane, allowing EBV to enter the B&nbsp;cell.<ref name=pmid-21233512/> Human CD35, also known as [[complement receptor 1]] (CR1), is an additional attachment factor for gp350 / 220, and can provide a route for entry of EBV into CD21-negative cells, including immature B-cells. EBV infection downregulates expression of CD35.<ref>{{cite journal | vauthors = Ogembo JG, Kannan L, Ghiran I, Nicholson-Weller A, Finberg RW, Tsokos GC, Fingeroth JD | title = Human complement receptor type&nbsp;1 / CD35 is an Epstein–Barr Virus receptor | journal = [[Cell Reports]] | volume = 3 | issue = 2 | pages = 371–85 | date = February 2013 | pmid = 23416052 | pmc = 3633082 | doi = 10.1016/j.celrep.2013.01.023 }}</ref>
To enter epithelial cells, viral protein BMRF-2  interacts with cellular β1 [[integrins]]. Then, viral protein gH/gL interacts with cellular [[αvβ6]]/[[αvβ8]] integrins. This triggers [[lipid bilayer fusion|fusion]] of the viral envelope with the epithelial cell membrane, allowing EBV to enter the epithelial cell.<ref name=pmid-21233512/> Unlike B-cell entry, epithelial-cell entry is actually impeded by viral glycoprotein gp42.<ref name=Entrez-CR2/>
Once EBV enters the cell, the viral capsid dissolves and the viral genome is transported to the [[cell nucleus]].<ref>{{cite journal | vauthors = Buschle A, Hammerschmidt W | title = Epigenetic lifestyle of Epstein–Barr virus | journal = Seminars in Immunopathology | volume = 42 | issue = 2 | pages = 131–142 | date = April 2020 | pmid = 32232535 | pmc = 7174264 | doi = 10.1007/s00281-020-00792-2 }}</ref>
====Lytic replication====
The [[lytic cycle]], or productive infection, results in the production of infectious [[virions]]. EBV can undergo lytic replication in both B&nbsp;cells and epithelial cells. In B&nbsp;cells, lytic replication normally only takes place after reactivation from [[#Latency|latency]]. In epithelial cells, lytic replication often directly follows [[#Entry to the cell|viral entry]].<ref name=pmid-21233512/>
For lytic replication to occur, the viral genome must be linear. The latent EBV genome is circular, so it must linearize in the process of lytic reactivation. During lytic replication, viral [[DNA polymerase]] is responsible for copying the viral genome. This contrasts with latency, in which host-cell DNA polymerase copies the viral genome.<ref name=pmid-21233512/>
Lytic gene products are produced in three consecutive stages: immediate-early, early, and late.<ref name=pmid-21233512/>
Immediate-early lytic gene products act as [[transactivators]], enhancing the [[gene expression|expression]] of later lytic genes. Immediate-early lytic gene products include [[BZLF1]] (also known as Zta, EB1, associated with its product gene ''ZEBRA'') and [[BRLF1]] (associated with its product gene ''Rta'').<ref name=pmid-21233512/>
Early lytic gene products have many more functions, such as replication, metabolism, and blockade of [[antigen processing]]. Early lytic gene products include [[BNLF2]].<ref name=pmid-21233512/>
Finally, late lytic gene products tend to be proteins with structural roles, such as [[Epstein–Barr virus viral capsid antigen|VCA]], which forms the viral [[capsid]]. Other late lytic gene products, such as BCRF1, help EBV evade the immune system.<ref name=pmid-21233512/>
[[EGCG]], a [[polyphenol]] in [[green tea]], has shown in a study to inhibit EBV spontaneous lytic infection at the DNA, gene transcription, and protein levels in a time- and [[dose-dependent]] manner; the expression of EBV lytic genes'' Zta, Rta'', and early antigen complex EA-D (induced by ''Rta''), however, the highly stable ''[[EBNA-1]]'' gene found across all stages of EBV infection is unaffected.<ref name=pmid-23180656>{{cite journal | vauthors = Liu S, Li H, Chen L, Yang L, Li L, Tao Y, Li W, Li Z, Liu H, Tang M, Bode AM, Dong Z, Cao Y | title = (−)-Epigallocatechin-3-gallate inhibition of Epstein–Barr virus spontaneous lytic infection involves ERK1/2 and PI3-K/Akt signaling in EBV-positive cells | journal = [[Carcinogenesis (journal)|Carcinogenesis]] | volume = 34 | issue = 3 | pages = 627–637 | date = March 2013 | pmid = 23180656 | doi = 10.1093/carcin/bgs364 }}</ref> Specific inhibitors (to the pathways) suggest that [[MAPK/ERK pathway|Ras/MEK/MAPK pathway]] contributes to EBV lytic infection though BZLF1 and [[PI3-K]] pathway through BRLF1, the latter completely abrogating the ability of a BRLF1 [[Adenoviridae#Use in treatment of unrelated diseases|adenovirus vector]] to induce the lytic form of EBV infection.<ref name=pmid-23180656/> Additionally, the activation of some genes but not others is being studied to determine just how to induce immune destruction of latently infected B&nbsp;cells by use of either [[12-O-Tetradecanoylphorbol-13-acetate|TPA]] or [[sodium butyrate]].<ref name=pmid-23180656/>
====Latency====
[[File:EBV-cycle-in-immunodeficiency.jpg|thumb|385x385px|Development of Epstein–Barr Virus (EBV)-induced acquired immunodeficiency in patients with genetic susceptibility]]
Unlike lytic replication, [[virus latency|latency]] does not result in production of virions.<ref name=pmid-21233512/>
Instead, the EBV genome circular DNA resides in the [[cell nucleus]] as an [[episome]] and is copied by host-cell [[DNA polymerase]].<ref name=pmid-21233512/> It persists in the individual's {{nobr|[[memory B cell]]s}}.<ref name=pmid-15546128/><ref name=pmid-34239514/> Epigenetic changes such as DNA [[methylation]] and cellular [[chromatin]] constituents, suppress the majority of the viral genes in latently infected cells.<ref name=pmid-32232535>{{cite journal | vauthors = Buschle A, Hammerschmidt W | date = April 2020 | title = Epigenetic lifestyle of Epstein–Barr virus | journal = [[Seminars in Immunopathology]] | volume = 42 | issue = 2 | pages = 131–142 | pmid = 32232535 | pmc = 7174264 | doi = 10.1007/s00281-020-00792-2 }}</ref> Only a portion of EBV's genes are [[gene expression|expressed]], which support the latent state of the virus.<ref name=pmid-32232535/><ref name=pmid-15546128/><ref>{{cite journal | vauthors = Thorley-Lawson DA, Miyashita EM, Khan G | date = May 1996 | title = Epstein–Barr virus and the B&nbsp;cell: That's all it takes | journal = [[Trends in Microbiology]] | volume = 4 | issue = 5 | pages = 204–208 | pmid = 8727601 | doi = 10.1016/s0966-842x(96)90020-7 }}</ref>
Latent EBV expresses its genes in one of three patterns, known as latency programs. EBV can latently persist within {{nobr|[[B cell]]s}} and [[epithelial cells]], but different latency programs are possible in the two types of cell.<ref>{{Cite journal |last1=Merchant |first1=M. |last2=Swart |first2=R. |last3=Katzman |first3=R. B. |last4=Ikeda |first4=M. |last5=Ikeda |first5=A. |last6=Longnecker |first6=R. |last7=Dykstra |first7=M. L. |last8=Pierce |first8=S. K. |date=2001 |title=The effects of the Epstein–Barr virus latent membrane protein 2A on B cell function |url= |journal=International Reviews of Immunology |volume=20 |issue=6 |pages=805–835 |doi=10.3109/08830180109045591 |issn=0883-0185 |pmid=11913951}}</ref><ref>{{Cite journal |last1=Kikuchi |first1=Kentaro |last2=Inoue |first2=Harumi |last3=Miyazaki |first3=Yuji |last4=Ide |first4=Fumio |last5=Kojima |first5=Masaru |last6=Kusama |first6=Kaoru |date=2017 |title=Epstein–Barr virus (EBV)-associated epithelial and non-epithelial lesions of the oral cavity |url= |journal=The Japanese Dental Science Review |volume=53 |issue=3 |pages=95–109 |doi=10.1016/j.jdsr.2017.01.002 |issn=1882-7616 |pmc=5501733 |pmid=28725300}}</ref>
EBV can exhibit one of three latency programs: Latency I, Latency II, or Latency III. Each latency program leads to the production of a  limited, distinct set of viral [[proteins]] and viral [[RNAs]].<ref name=pmid-17446270>{{cite journal | vauthors = Calderwood MA, Venkatesan K, Xing L, Chase MR, Vazquez A, Holthaus AM, Ewence AE, Li N, Hirozane-Kishikawa T, Hill DE, Vidal M, Kieff E, Johannsen E | title = Epstein–Barr virus and virus human protein interaction maps | journal = [[Proceedings of the National Academy of Sciences of the United States of America]] | volume = 104 | issue = 18 | pages = 7606–11 | date = May 2007 | pmid = 17446270 | pmc = 1863443 | doi = 10.1073/pnas.0702332104 | bibcode = 2007PNAS..104.7606C | doi-access = free }} The nomenclature used here is that of Kieff. Other laboratories use different nomenclatures.</ref><ref name=pmid-19680535>{{cite journal | vauthors = Hutzinger R, Feederle R, Mrazek J, Schiefermeier N, Balwierz PJ, Zavolan M, Polacek N, Delecluse HJ, Hüttenhofer A | title = Expression and processing of a small nucleolar RNA from the Epstein-Barr virus genome | journal = [[PLOS Pathogens]] | volume = 5 | issue = 8 | pages = e1000547 | date = August 2009 | pmid = 19680535 | pmc = 2718842 | doi = 10.1371/journal.ppat.1000547 | doi-access = free }}</ref>
{| class="wikitable"
|-
! Gene Expressed !! [[EBNA-1]] !! [[EBNA-2]] !! [[EBNA-3]]A !! [[EBNA-3]]B !! [[EBNA-3]]C !! EBNA-LP !! [[Epstein–Barr virus latent membrane protein 1|LMP1]] !! [[LMP-2]]A !! [[LMP-2]]B !!  [[EBER]]
|-
| Product|| Protein || Protein || Protein || Protein || Protein || Protein || Protein || Protein || Protein || [[ncRNA]]s
|-
| '''Latency I'''||align="center"|+||align="center"|–||align="center"|–||align="center"|–||align="center"|–||align="center"|–||align="center"|–||align="center"|–||align="center"|–||align="center"|+
|-
| '''Latency II'''||align="center"|+||align="center"|–||align="center"|–||align="center"|–||align="center"|–||align="center"|+||align="center"|+||align="center"|+||align="center"|+||align="center"|+
|-
| '''Latency III'''||align="center"|+||align="center"|+||align="center"|+||align="center"|+||align="center"|+||align="center"|+||align="center"|+||align="center"|+||align="center"|+||align="center"|+
|}
Also, a program is postulated in which all viral protein expression is shut off (Latency 0).<ref>{{cite journal | vauthors = Plottel CS, Blaser MJ | date = October 2011 | title = Microbiome and malignancy | journal = Cell Host & Microbe | volume = 10 | issue = 4 | pages = 324–335 | pmid = 22018233 | pmc = 3264051 | doi = 10.1016/j.chom.2011.10.003 | author2-link = Martin J. Blaser }}</ref>
Within B&nbsp;cells, all three latency programs are possible.<ref name=pmid-15546128/> EBV latency within B&nbsp;cells usually progresses from Latency&nbsp;III to Latency&nbsp;II to Latency&nbsp;I. Each stage of latency uniquely influences B&nbsp;cell behavior.<ref name=pmid-15546128/> Upon infecting a resting [[naive B cell|naïve B&nbsp;cell]], EBV enters Latency&nbsp;III. The set of proteins and RNAs produced in Latency&nbsp;III transforms the B&nbsp;cell into a proliferating blast (also known as B&nbsp;cell activation).<ref name=pmid-15546128/><ref name=pmid-21233512/> Later, the virus restricts its gene expression and enters Latency&nbsp;II. The more limited set of proteins and RNAs produced in Latency&nbsp;II induces the B&nbsp;cell to differentiate into a [[memory B cell|memory B&nbsp;cell]].<ref name=pmid-15546128/><ref name=pmid-21233512/> Finally, EBV restricts gene expression even further and enters Latency&nbsp;I. Expression of EBNA-1 allows the EBV genome to replicate when the memory B&nbsp;cell divides.<ref name=pmid-15546128/><ref name=pmid-21233512/>
Within epithelial cells, only Latency&nbsp;II is possible.<ref>{{cite journal | vauthors = Ansari MA, Singh VV, Dutta S, Veettil MV, Dutta D, Chikoti L, Lu J, Everly D, Chandran B | date = August 2013 | title = Constitutive interferon-inducible protein 16-inflammasome activation during Epstein–Barr virus latency&nbsp;I, II, and III in B and epithelial cells | journal = [[Journal of Virology]] | volume = 87 | issue = 15 | pages = 8606–8623 | pmid = 23720728 | pmc = 3719826 | doi = 10.1128/JVI.00805-13 }}</ref>
In primary infection, EBV replicates in oropharyngeal epithelial cells and establishes Latency&nbsp;III, II, and I infections in B&nbsp;lymphocytes. EBV latent infection of B&nbsp;lymphocytes is necessary for virus persistence, subsequent replication in epithelial cells, and release of infectious virus into saliva. EBV Latency&nbsp;III and II infections of B&nbsp;lymphocytes, Latency&nbsp;II infection of oral epithelial cells, and Latency&nbsp;II infection of NK- or T-cell can result in malignancies, marked by uniform EBV genome presence and gene expression.<ref name=Robertsones>{{Cite book |veditors = Robertson ES | year=2010 |title=Epstein–Barr Virus: Latency and Transformation| publisher=[[Caister Academic Press]] | isbn= 978-1-904455-62-2}}</ref>
====Reactivation====
Latent EBV in B&nbsp;cells can be reactivated to switch to [[#Lytic replication|lytic replication]]. This is known to happen ''[[in vivo]]'', but what triggers it is not known precisely. ''In vitro'', latent EBV in B&nbsp;cells can be reactivated by stimulating the B&nbsp;cell receptor, so it is likely reactivation ''[[in vivo]]'' takes place after latently infected B&nbsp;cells respond to unrelated infections.<ref name=pmid-21233512/>
===Transformation of B&nbsp;lymphocytes===
EBV infection of B&nbsp;lymphocytes leads to "[[Biological immortality|immortalization]]" of these cells, meaning that the virus causes them to continue dividing indefinitely. Normally, cells have a limited lifespan and eventually die, but when EBV infects B&nbsp;lymphocytes, it alters their behavior, making them "immortal" in the sense that they can keep dividing and surviving much longer than usual. This allows the virus to persist in the body for the individual's lifetime.<ref name="pmid31315893"/>
When EBV infects B&nbsp;cells ''[[in vitro]]'', [[lymphoblastoid]] cell lines eventually emerge that are capable of indefinite growth. The growth transformation of these cell lines is the consequence of viral protein expression.<ref>{{cite journal | vauthors = Münz C | date = November 2019 | title = Latency and lytic replication in Epstein–Barr virus-associated oncogenesis | journal = Nature Reviews Microbiology | volume = 17 | issue = 11 | pages = 691–700 | pmid = 31477887 | doi = 10.1038/s41579-019-0249-7 | s2cid = 201713873 | url = https://www.zora.uzh.ch/id/eprint/183065/9/latecny_and_lytic_replication_in_the_oncogenesis_of_the_epstein-barr_virus_final_manuscript.pdf | access-date = 19 April 2023 | archive-date = 8 October 2023 | archive-url = https://web.archive.org/web/20231008005820/https://www.zora.uzh.ch/id/eprint/183065/9/latecny_and_lytic_replication_in_the_oncogenesis_of_the_epstein-barr_virus_final_manuscript.pdf | url-status = live }}</ref>
EBNA-2, EBNA-3C, and LMP-1, are essential for transformation, whereas EBNA-LP and the EBERs are not.<ref name=Yates1985>{{cite journal | vauthors = Yates JL, Warren N, Sugden B | year = 1985 | title = Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells | journal = [[Nature (journal)|Nature]] | volume = 313 | issue = 6005 | pages = 812–815 | pmid = 2983224 | doi = 10.1038/313812a0 | bibcode = 1985Natur.313..812Y | s2cid = 4334367 }}</ref>
Following natural infection with EBV, the virus is thought to execute some or all of its repertoire of gene expression programs to establish a persistent infection. Given the initial absence of host [[Immunity (medical)|immunity]], the lytic cycle produces large numbers of virions to infect other (presumably) B-lymphocytes within the host.
The latent programs reprogram and subvert infected B-lymphocytes to proliferate and bring infected cells to the sites at which the virus presumably persists. Eventually, when host immunity develops, the virus persists by turning off most (or possibly all) of its genes and only occasionally reactivates and produces progeny virions. A balance is eventually struck between occasional viral reactivation and host immune surveillance removing cells that activate viral gene expression. The manipulation of the human body's epigenetics by EBV can alter the genome of the cell to leave oncogenic phenotypes.<ref name=pmid-19740997/> As a result, the modification by the EBV increases the hosts likelihood of developing EBV related cancer.<ref name=pmid-27933614/> EBV related cancers are unique in that they are frequent to making epigenetic changes but are less likely to mutate.<ref name=pmid-28780440>{{cite journal | vauthors = Scott RS | title = Epstein–Barr virus: A master epigenetic manipulator | journal = [[Current Opinion in Virology]] | volume = 26 | pages = 74–80 | date = October 2017 | pmid = 28780440 | pmc = 5742862 | doi = 10.1016/j.coviro.2017.07.017 }}</ref>
The site of persistence of EBV may be [[bone marrow]]. EBV-positive patients who have had their own bone marrow replaced with bone marrow from an EBV-negative donor are found to be EBV-negative after [[Organ transplant|transplantation]].<ref name=Gratama1988>{{cite journal | vauthors = Gratama JW, Oosterveer MA, Zwaan FE, Lepoutre J, Klein G, Ernberg I | date = November 1988 | title = Eradication of Epstein–Barr virus by allogeneic bone marrow transplantation: implications for sites of viral latency | journal = [[Proceedings of the National Academy of Sciences of the United States of America]] | volume = 85 | issue = 22 | pages = 8693–8696 | pmid = 2847171 | pmc = 282526 | doi = 10.1073/pnas.85.22.8693 | bibcode = 1988PNAS...85.8693G | doi-access = free }}</ref>
=== Latent antigens ===
All EBV nuclear proteins are produced by alternative splicing of a transcript starting at either the Cp or Wp promoters at the left end of the [[genome]] (in the conventional nomenclature). The genes are ordered ''EBNA-LP/EBNA-2/EBNA-3A/EBNA-3B/EBNA-3C/EBNA-1'' within the genome.
The initiation [[codon]] of the EBNA-LP coding region is created by an alternate splice of the nuclear protein transcript. In the absence of this initiation codon,'' EBNA-2/EBNA-3A/EBNA-3B/EBNA-3C/EBNA-1'' will be expressed depending on which of these genes is alternatively spliced into the transcript.
===Protein/genes===
{| class="wikitable"
|-
! Protein/gene/antigen
! Stage
! Description
|-
| '''[[Epstein–Barr virus nuclear antigen 1|EBNA-1]]'''
| latent+lytic
| EBNA-1 protein binds to a replication origin (oriP) within the viral genome and mediates replication and partitioning of the episome during division of the host cell. It is the only viral protein expressed during group I latency.
|-
| '''[[Epstein–Barr virus nuclear antigen 2|EBNA-2]]'''
| latent+lytic
| EBNA-2 is the main viral [[transactivator]].
|-
| '''[[Epstein–Barr virus nuclear antigen 3|EBNA-3]]'''
| latent+lytic
| These genes also bind the host [[RBPJ|RBP-Jκ]] protein.
|-
| '''[[Epstein–Barr virus latent membrane protein 1|LMP-1]]'''
| latent
| LMP-1 is a six-span [[transmembrane]] protein that is also essential for EBV-mediated growth transformation.
|-
| '''[[Epstein–Barr virus latent membrane protein 2|LMP-2]]'''
| latent
| LMP-2A/LMP-2B are transmembrane proteins that act to block [[tyrosine kinase]] signaling.
|-
| '''[[Epstein–Barr virus-encoded small RNAs|EBER]]'''
| latent
| EBER-1/EBER-2 are small nuclear RNAs, which bind to certain nucleoprotein particles, enabling binding to PKR (dsRNA-dependent serin/threonin protein kinase), thus inhibiting its function. EBERs are by far the most abundant EBV products transcribed in EBV-infected cells. They are commonly used as targets for the detection of EBV in histological tissues.<ref name=khan>{{cite journal | vauthors = Khan G, Coates PJ, Kangro HO, Slavin G | date = July 1992 | title = Epstein Barr virus (EBV) encoded small RNAs: Targets for detection by ''in situ'' hybridisation with oligonucleotide probes | journal = [[Journal of Clinical Pathology]] | volume = 45 | issue = 7 | pages = 616–620 | pmid = 1325480 | pmc = 495191 | doi = 10.1136/jcp.45.7.616 }}</ref> ER-particles also induce the production of IL-10, which enhances growth and inhibits cytotoxic T&nbsp;cells.
|-
| '''[[Epstein–Barr virus small nucleolar RNA 1|v-snoRNA1]]'''
| latent
| [[Epstein–Barr virus small nucleolar RNA 1|Epstein–Barr virus snoRNA1]] is a box CD-snoRNA generated by the virus during latency. V-snoRNA1 may act as a miRNA-like precursor that is processed into 24&nbsp;nucleotide sized RNA fragments that target the 3'UTR of viral DNA polymerase mRNA.<ref name=pmid-19680535/>
|-
| '''[[Epstein–Barr virus stable intronic-sequence RNAs|ebv-sisRNA]]'''
| latent
| Ebv-sisRNA-1 is a stable intronic sequence RNA generated during latency program III. After the [[EBER]]s, it is the third-most abundant small RNA produced by the virus during this program.<ref name=Moss2013>{{cite journal | vauthors = Moss WN, Steitz JA | date = August 2013 | title = Genome-wide analyses of Epstein–Barr virus reveal conserved RNA structures and a novel stable intronic sequence RNA | journal = [[BMC Genomics]] | volume = 14 | page = 543 | pmid = 23937650 | pmc = 3751371 | doi = 10.1186/1471-2164-14-543 | doi-access = free }}</ref>
|-
| '''miRNAs'''
| latent
| EBV microRNAs are encoded by two transcripts, one set in the ''BART'' gene and one set near the'' BHRF1'' cluster. The three ''BHRF1'' pri-miRNAS (generating four miRNAs) are expressed during type III latency, whereas the large cluster of ''BART'' miRNAs (up to 20 miRNAs) are expressed highly during type II latency and only modestly during type I and II latency.<ref name=Forte2011>{{cite journal | vauthors = Forte E, Luftig MA | date = December 2011 | title = The role of microRNAs in Epstein–Barr virus latency and lytic reactivation | journal = Microbes Infect | volume = 13 | issue = 14,15 | pages = 1156–1167 | pmid = 21835261 | doi = 10.1016/j.micinf.2011.07.007 | pmc = 4911174 }}</ref> The previous reference also gives an account of the known functions of these miRNAs.
|-
| [[EBV-EA]]
| lytic
| early antigen
|-
| [[EBV-MA]]
| lytic
| membrane antigen
|-
| [[Epstein–Barr virus viral-capsid antigen|EBV-VCA]]
| lytic
| viral capsid antigen
|-
| EBV-AN
| lytic
| alkaline nuclease<ref name=Buisson2009>{{cite journal | vauthors = Buisson M, Géoui T, Flot D, Tarbouriech N, Ressing ME, Wiertz EJ, Burmeister WP | date = August 2009 | title = A bridge crosses the active-site canyon of the Epstein–Barr virus nuclease with DNase and RNase activities | journal = [[Journal of Molecular Biology]] | volume = 391 | issue = 4 | pages = 717–728 | pmid = 19538972 | doi = 10.1016/j.jmb.2009.06.034 }}</ref>
|}
===Subtypes of EBV===
EBV can be divided into two major types, EBV type&nbsp;1 and EBV type&nbsp;2. These two subtypes have different [[EBNA-3]] genes. As a result, the two subtypes differ in their transforming capabilities and reactivation ability. Type&nbsp;1 is dominant throughout most of the world, but the two types are equally prevalent in [[Africa]]. One can distinguish EBV type&nbsp;1 from EBV type&nbsp;2 by cutting the viral genome with a [[restriction enzyme]] and comparing the resulting digestion patterns by [[gel electrophoresis]].<ref name=pmid-21233512/>
==Detection==
{| class="wikitable floatright"
|+Interpretation of specific EBV antibodies
!Typical interpretation
!VCA-IgG
!VCA-IgM
!EA
!EBNA
|-
|Never infected
| –
| –
| –
| –
|-
|Acute infection (IM)
| +
| +
| +/−
| –
|-
|Acute or recent infection
| +
| +/−
| +
| +/−
|-
|Recent past infection
| +
| –
| +/−
| +
|-
|Distant past infection
| +
| –
| –
| +
|-
|Chronic infection/reactivation
| +
| –
| +
| +/−
|}
{{Expand section|date=March 2022}}
Epstein–Barr virus-encoded small RNAs (EBERs) are by far the most abundant EBV products transcribed in cells infected by EBV. They are commonly used as targets for the detection of EBV in histological tissues.<ref name=khan/>
Clinically, the most common way to detect the presence of EBV is [[ELISA|enzyme-linked immuno sorbent assay]] (ELISA). [[Antibody|Antibodies]] (IgM and IgG) to [[protein]]s encoded by the EBV DNA are detected.<ref>{{Cite journal |last1=Matheson |first1=B A |last2=Chisholm |first2=S M |last3=Ho-Yen |first3=D O |date=August 1990 |title=Assessment of rapid ELISA test for detection of Epstein–Barr virus infection. |journal=Journal of Clinical Pathology |volume=43 |issue=8 |pages=691–693 |doi=10.1136/jcp.43.8.691 |issn=0021-9746 |pmid=2169485|pmc=502656 }}</ref> Direct detection of EBV genome presence via [[polymerase chain reaction]] (PCR) is seldom done, as this method says nothing about the immune system's reaction to the virus. EBV viral load does not correlate well with clinical symptoms of infection.<ref>{{Cite journal |last1=Kimura |first1=Hiroshi |last2=Kwong |first2=Yok-Lam |date=2019-02-12 |title=EBV Viral Loads in Diagnosis, Monitoring, and Response Assessment |journal=Frontiers in Oncology |volume=9 |pages=62 |doi=10.3389/fonc.2019.00062 |doi-access=free |issn=2234-943X |pmc=6379266 |pmid=30809508}}</ref>
== Role in disease ==
:''See also [[Infectious mononucleosis]] and the other diseases listed in this section''
EBV causes infectious mononucleosis.<ref>{{cite journal | vauthors = Weiss LM, O'Malley D | date = January 2013 | title = Benign lymphadenopathies | journal = [[Modern Pathology]] | volume = 26 | issue = Supplement&nbsp;1 | pages = S88–S96 | pmid = 23281438 | doi = 10.1038/modpathol.2012.176 | doi-access = free }}</ref> Children infected with EBV have few symptoms or can appear asymptomatic, but when infection is delayed to adolescence or adulthood, it can cause [[Fatigue (medical)|fatigue]], [[fever]], [[Pharyngitis|inflamed throat]], [[Lymphadenopathy|swollen]] [[lymph node]]s in the neck, [[Splenomegaly|enlarged spleen]], [[Hepatomegaly|swollen liver]], or rash.<ref name="CDC–2020-09-28-mono"/> Post-infectious [[ME/CFS|chronic fatigue syndrome]] has also been associated with EBV infection.<ref name=pmid-2855828>{{cite journal | vauthors = Schooley RT | title = Chronic fatigue syndrome: A manifestation of Epstein–Barr virus infection? | journal = [[Current Clinical Topics in Infectious Diseases]] | volume = 9 | issue = | pages = 126–146 | date = 1988 | pmid = 2855828 | doi = | url = }}</ref><ref>{{cite journal | vauthors = Proal AD, VanElzakker MB | date = 23 June 2021 | title = Long COVID or post-acute sequelae of COVID-19 (PASC): An overview of biological factors that may contribute to persistent symptoms | journal = [[Frontiers in Microbiology]] | volume = 12 | page = 698169 | pmid = 34248921 | pmc = 8260991 | doi = 10.3389/fmicb.2021.698169 | doi-access = free }}</ref>
EBV has also been implicated in several other diseases, including [[Burkitt's lymphoma]],<ref>{{cite journal | vauthors = Pannone G, Zamparese R, Pace M, Pedicillo MC, Cagiano S, Somma P, Errico ME, Donofrio V, Franco R, de Chiara A, Aquino G, Bucci P, Bucci E, Santoro A, Bufo P | year = 2014 | title = The role of EBV in the pathogenesis of Burkitt's Lymphoma: an Italian hospital based survey | journal = [[Infectious Agents and Cancer]] | volume = 9 | issue = 1 | page = 34 | pmid = 25364378 | pmc = 4216353 | doi = 10.1186/1750-9378-9-34 | doi-access = free }}</ref> [[hemophagocytic lymphohistiocytosis]],<ref name=pmid-29358936>{{cite journal | vauthors = Marsh RA | year = 2017 | title = Epstein–Barr virus and hemophagocytic lymphohistiocytosis | journal = [[Frontiers in Immunology]] | volume = 8 | page = 1902 | pmid = 29358936 | pmc = 5766650 | doi = 10.3389/fimmu.2017.01902 | doi-access = free }}</ref> [[Hodgkin's lymphoma]],<ref>{{cite journal | vauthors = Gandhi MK, Tellam JT, Khanna R | date = May 2004 | title = Epstein–Barr virus-associated Hodgkin's lymphoma | journal = [[British Journal of Haematology]] | volume = 125 | issue = 3 | pages = 267–281 | pmid = 15086409 | doi = 10.1111/j.1365-2141.2004.04902.x | doi-access = free | s2cid = 2355660 }}</ref> [[stomach cancer]],<ref name=Cancer-Research-UK-200000>{{cite press release |title=Developing a vaccine for the Epstein–Barr virus could prevent up to 200,000&nbsp;cancers globally say experts |date=2014-03-24 |website=[[Cancer Research UK]] |url=https://www.cancerresearchuk.org/about-us/cancer-news/press-release/2014-03-24-developing-a-vaccine-for-the-epstein-barr-virus-could-prevent-up-to-200000-cancers-globally-say |url-status=live |archive-url=https://web.archive.org/web/20170319073808/http://www.cancerresearchuk.org/about-us/cancer-news/press-release/2014-03-24-developing-a-vaccine-for-the-epstein-barr-virus-could-prevent-up-to-200000-cancers-globally-say |archive-date=2017-03-19}}</ref><ref>{{cite journal | vauthors = Yau TO, Tang CM, Yu J | date = June 2014 | title = Epigenetic dysregulation in Epstein–Barr virus-associated gastric carcinoma: Disease and treatments | journal = [[World Journal of Gastroenterology]] | volume = 20 | issue = 21 | pages = 6448–6456 | pmid = 24914366 | pmc = 4047330 | doi = 10.3748/wjg.v20.i21.6448 | doi-access = free }}</ref> [[nasopharyngeal carcinoma]],<ref>{{cite journal | vauthors = Dogan S, Hedberg ML, Ferris RL, Rath TJ, Assaad AM, Chiosea SI | date = April 2014 | title = Human papillomavirus and Epstein–Barr virus in nasopharyngeal carcinoma in a low-incidence population | journal = Head & Neck | volume = 36 | issue = 4 | pages = 511–516 | pmid = 23780921 | pmc = 4656191 | doi = 10.1002/hed.23318 }}</ref> [[multiple sclerosis]],<ref name=pmid-35025605/><ref name=pmid-20369303/><ref name=pmid-25740864>{{cite journal | vauthors = Mechelli R, Manzari C, Policano C, Annese A, Picardi E, Umeton R, Fornasiero A, D'Erchia AM, Buscarinu MC, Agliardi C, Annibali V, Serafini B, Rosicarelli B, Romano S, Angelini DF, Ricigliano VA, Buttari F, Battistini L, Centonze D, Guerini FR, D'Alfonso S, Pesole G, Salvetti M, Ristori G | date = March 2015 | title = Epstein–Barr virus genetic variants are associated with multiple sclerosis | journal = [[Neurology (journal)|Neurology]] | volume = 84 | issue = 13 | pages = 1362–1368 | pmid = 25740864 | pmc = 4388746 | doi = 10.1212/WNL.0000000000001420 }}</ref><ref name=pmid-29892607>{{cite journal | vauthors = Moreno MA, Or-Geva N, Aftab BT, Khanna R, Croze E, Steinman L, Han MH | date = July 2018 | title = Molecular signature of Epstein–Barr virus infection in MS brain lesions | journal = [[Neurology (journal)|Neurology]] | volume = 5 | issue = 4 | page = e466 | pmid = 29892607 | pmc = 5994704 | doi = 10.1212/NXI.0000000000000466 }}</ref> and [[lymphomatoid granulomatosis]].<ref>{{cite journal | vauthors = Tagliavini E, Rossi G, Valli R, Zanelli M, Cadioli A, Mengoli MC, Bisagni A, Cavazza A, Gardini G | date = August 2013 | title = Lymphomatoid granulomatosis: A practical review for pathologists dealing with this rare pulmonary lymphoproliferative process | journal = [[Pathologica]] | volume = 105 | issue = 4 | pages = 111–116 | pmid = 24466760 }}</ref>
Specifically, EBV infected B&nbsp;cells have been shown to reside within the brain lesions of [[multiple sclerosis]] patients,<ref name=pmid-29892607/> and a 2022 study of 10&nbsp;million soldiers' historical blood samples showed that "Individuals who were not infected with the Epstein–Barr virus virtually never get multiple sclerosis. It's only after Epstein–Barr virus infection that the risk of multiple sclerosis jumps up by over 30 fold", and that only EBV of many infections had such a clear connection with the disease.<ref>{{cite news |title=Is a virus we all have causing multiple sclerosis? |date=13 April 2022 |website=[[BBC News]] |url=https://www.bbc.com/news/health-61042598 |access-date=29 April 2022 |archive-date=25 April 2022 |archive-url=https://web.archive.org/web/20220425142547/https://www.bbc.com/news/health-61042598 |url-status=live }}</ref>
Additional diseases that have been linked to EBV include [[Gianotti–Crosti syndrome]], [[erythema multiforme]], acute genital ulcers, and [[oral hairy leukoplakia]].<ref>{{cite journal | vauthors = di Lernia V, Mansouri Y | date = October 2013 | title = Epstein–Barr virus and skin manifestations in childhood | journal = [[International Journal of Dermatology]] | volume = 52 | issue = 10 | pages = 1177–1184 | pmid = 24073903 | doi = 10.1111/j.1365-4632.2012.05855.x | s2cid = 30557756 | doi-access = free }}</ref> The viral infection is also associated with, and often contributes to the development of, a wide range of non-malignant [[Epstein–Barr virus-associated lymphoproliferative diseases|lymphoproliferative diseases]] such  as severe hypersensitivity [[mosquito bite allergy]] reactions,<ref name=pmid-27900557>{{cite journal | vauthors = Kyriakidis I, Vasileiou E, Karastrati S, Tragiannidis A, Gompakis N, Hatzistilianou M | date = December 2016 | title = Primary EBV infection and hypersensitivity to mosquito bites: a case report | journal = [[Virologica Sinica]] | volume = 31 | issue = 6 | pages = 517–520 | pmid = 27900557 | doi = 10.1007/s12250-016-3868-4 | s2cid = 7996104 | pmc = 8193400 }}</ref> [[Epstein–Barr virus-associated lymphoproliferative diseases#Epstein–Barr virus-positive mucocutaneous ulcer|Epstein–Barr virus-positive mucocutaneous ulcer]]s, and [[Epstein–Barr virus-associated lymphoproliferative diseases#Hydroa vacciniforme-like lymphoproliferative disease|hydroa vacciniforme]] as well as malignant lymphoproliferative diseases such as [[Epstein–Barr virus-associated lymphoproliferative diseases#Epstein–Barr virus-positive Burkitt lymphoma|Epstein–Barr virus-positive Burkitt lymphoma]],<ref name=pmid-26113842>{{cite journal | vauthors = Navari M, Etebari M, de Falco G, Ambrosio MR, Gibellini D, Leoncini L, Piccaluga PP | year = 2015 | title = The presence of Epstein–Barr virus significantly impacts the transcriptional profile in immunodeficiency-associated Burkitt lymphoma | journal = [[Frontiers in Microbiology]] | volume = 6 | page = 556 | pmid = 26113842 | pmc = 4462103 | doi = 10.3389/fmicb.2015.00556 | doi-access = free }}</ref> [[Epstein–Barr virus-associated lymphoproliferative diseases#Epstein–Barr virus-positive Hodgkin lymphoma|Epstein–Barr virus-positive Hodgkin lymphoma]],<ref name=pmid-28893938>{{cite journal | vauthors = Shannon-Lowe C, Rickinson AB, Bell AI | date = October 2017 | title = Epstein–Barr virus-associated lymphomas | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 372 | issue = 1732 | page = 20160271 | pmid = 28893938 | pmc = 5597738 | doi = 10.1098/rstb.2016.0271 }}</ref> and [[primary effusion lymphoma]].<ref name=pmid-28399009>{{cite journal | vauthors = Arora N, Gupta A, Sadeghi N | date = July 2017 | title = Primary effusion lymphoma: Current concepts and management | journal = [[Current Opinion in Pulmonary Medicine]] | volume = 23 | issue = 4 | pages = 365–370 | pmid = 28399009 | doi = 10.1097/MCP.0000000000000384 | s2cid = 4514140 }}</ref>
The Epstein–Barr virus has been implicated  in disorders related to [[alpha-synuclein]] aggregation (e.g. [[Parkinson's disease]], [[dementia with Lewy bodies]], and [[multiple system atrophy]]).<ref>{{cite journal | vauthors = Woulfe J, Hoogendoorn H, Tarnopolsky M, Muñoz DG | date = November 2000 | title = Monoclonal antibodies against Epstein–Barr virus cross-react with alpha-synuclein in human brain | journal = [[Neurology (journal)|Neurology]] | volume = 55 | issue = 9 | pages = 1398–1401 | pmid = 11087792 | doi = 10.1212/WNL.55.9.1398 | s2cid = 84387269 }}</ref>
It has been found that [[EBNA1]] may induce chromosomal breakage in the [[Chromosome 11|11th chromosome]], specifically in the 11q23 region between the FAM55D gene and FAM55B, which EBNA-1 appears to have a high affinity for due to its [[DNA-binding domain]] having an interest in a specific [[Palindromic sequence|palindromic repeat]] in this section of the genome.<ref>{{Cite journal |last=Frappier |first=Lori |date=April 2023 |title=Epstein–Barr virus is an agent of genomic instability |url=https://www.nature.com/articles/d41586-023-00936-y |journal=[[Nature (journal)|Nature]] |language=en |volume=616 |issue=7957 |pages=441–442 |doi=10.1038/d41586-023-00936-y|pmid=37045952 |bibcode=2023Natur.616..441F |s2cid=258110880 }}</ref> While the cause and exact mechanism for this is unknown, the byproduct results in errors and breakage of the chromosomal structure as cells stemming from the line of the tainted genome undergo [[mitosis]]. Since genes in this area have been implicated in [[leukemia]] and is home to a [[Ataxia telangiectasia mutated|tumor suppressor gene]] that is modified or not present in most tumor gene expression, it's been hypothesized that breakage in this area is the main culprit behind the cancers that EBV increases the chance of. The breakage is also dose-dependent, a person with a latent infection will have less breakage than a person with a novel or reactivated infection since EBNA1 levels in the nucleus and nucleolus are higher during active attack of the body because of the constant replication and take-over of cells in the body.
The complexities of Epstein-Barr virus (EBV) persistence and its integration into host genomes have been explored. Research involving tissue samples from individuals with various conditions revealed that viral sequences were highly conserved, indicating long-term persistence from dominant strains. Notably, EBV was found to integrate into the host genome in cases of malignancies, including mantle cell lymphoma, where a significant integration event was observed involving the EBV LMP-1 gene and chromosome 17. This integration likely occurred via microhomology-mediated end joining, suggesting a potential mechanism through which EBV may influence tumorigenesis. Moreover, instances of high viral loads and accompanying genetic diversity were noted in patients with active disease, underscoring the virus's dynamic nature within the host and its possible contribution to the progression of EBV-associated cancers.<ref name="Pyoria2024">{{cite journal | vauthors = Pyöriä L, Pratas D, Toppinen M, Simmonds P, Hedman K, Sajantila A, Perdomo M | title = Intra-host genomic diversity and integration landscape of human tissue-resident DNA virome | journal = Nucleic Acids Research | year = 2024 | volume = 52 | issue = 21 | pages = gkae871 | doi = 10.1093/nar/gkae871 | pmid = 39436041| doi-access = free | pmc = 11602146 }}</ref>
== History ==
The Epstein–Barr virus was named after [[Michael A. Epstein|M.A. Epstein]] and [[Yvonne Barr]], who discovered the virus together with [[Bert Achong]].<ref>{{cite news |vauthors = McGrath P |date=6 April 2014 |title=Cancer virus discovery helped by delayed flight |website=[[BBC News]] |department=Health |url=https://www.bbc.co.uk/news/health-26857610 |access-date=4 November 2015 |url-status=live |archive-url=https://web.archive.org/web/20151008021944/http://www.bbc.co.uk/news/health-26857610 |archive-date=8 October 2015}}</ref><ref name=pmid-14107961>{{cite journal | vauthors = Epstein MA, Achong BG, Barr YM | date = March 1964 | journal = [[Lancet (journal)|Lancet]] | volume = 1 | issue = 7335 | pages = 702–703 | pmid = 14107961 | doi = 10.1016/s0140-6736(64)91524-7 | title = Virus Particles in Cultured Lymphoblasts from Burkitt's Lymphoma }}</ref> In 1961, Epstein, a [[pathologist]] and expert [[electron microscope|electron microscopist]], attended a lecture on "The commonest children's cancer in tropical Africa—a hitherto unrecognised syndrome" by [[Denis Parsons Burkitt|D. P. Burkitt]], a surgeon practicing in [[Uganda]], in which Burkitt described the "endemic variant" (pediatric form) of the disease that [[Burkitt's lymphoma|now bears his name]]. In 1963, a specimen was sent from Uganda to [[Middlesex Hospital]] to be cultured. Virus particles were identified in the cultured cells, and the results were published in ''[[The Lancet]]'' in 1964 by Epstein, Achong, and Barr.<ref name=pmid-14107961/><ref name=Epstein-2005/> Cell lines were sent to [[Werner and Gertrude Henle]] at the [[Children's Hospital of Philadelphia]] who developed [[serology|serological]] markers.<ref name=pmid-6261650/> In 1967, a technician in their laboratory developed mononucleosis and they were able to compare a stored serum sample, showing that [[antibody|antibodies]] to the virus developed.<ref name=Epstein-2005>{{cite book |vauthors = Epstein MA |author-link = M. Anthony Epstein |year = 2005 |chapter = 1.&nbsp;The origins of EBV research: Discovery and characterization of the virus |veditors = Robertson ES |title = Epstein–Barr Virus |publisher = Caister Academic Press |place = Wymondham, UK |isbn = 978-1-904455-03-5 |pages = 1–14 |chapter-url = https://books.google.com/books?id=TRO-wXto8hcC |access-date = September 18, 2010 |archive-date = 10 January 2023 |archive-url = https://web.archive.org/web/20230110010611/https://books.google.com/books?id=TRO-wXto8hcC |url-status = live }}</ref><ref>{{cite book |vauthors=Robertson ES |year=2005 |title=Epstein–Barr Virus |publisher=Horizon Scientific Press |isbn=978-1-904455-03-5 |page=18 |url=https://books.google.com/books?id=TRO-wXto8hcC |access-date=3 June 2012 |archive-date=10 January 2023 |archive-url=https://web.archive.org/web/20230110010611/https://books.google.com/books?id=TRO-wXto8hcC |url-status=live }}</ref><ref>{{cite journal | vauthors = Miller G |date = 21 December 2006 |type=book review |title=''Epstein–Barr Virus'' |journal= [[New England Journal of Medicine]] |volume= 355 |issue= 25 |pages= 2708–2709 |doi= 10.1056/NEJMbkrev39523 }}</ref> In 1968, they discovered that EBV can directly [[Immortalised cell line|immortalize]] B&nbsp;cells after infection,<ref name="pmid31315893">{{cite journal |vauthors=Kerr JR |title=Epstein-Barr virus (EBV) reactivation and therapeutic inhibitors |journal=J Clin Pathol |volume=72 |issue=10 |pages=651–658 |date=October 2019 |pmid=31315893 |doi=10.1136/jclinpath-2019-205822}}</ref> mimicking some forms of EBV-related infections,<ref name=pmid-6261650>{{cite journal | vauthors = Henle W, Henle G | year = 1980 | title = Epidemiologic aspects of Epstein–Barr virus (EBV)-associated diseases | journal = [[Annals of the New York Academy of Sciences]] | volume = 354 | pages = 326–331 | pmid = 6261650 | doi = 10.1111/j.1749-6632.1980.tb27975.x | s2cid = 30025994 }}</ref> and confirmed the link between the virus and infectious mononucleosis.<ref>{{cite book | vauthors = Young LS |year=2009 |title=Desk Encyclopedia of Human and Medical Virology |publisher=Academic Press |location=Boston, MA |pages=532–533}}</ref>
==Research==
As a relatively complex virus, EBV is not yet fully understood. Laboratories around the world continue to study the virus and develop new ways to treat the diseases it causes. One popular way of studying EBV ''[[in vitro]]'' is to use [[bacterial artificial chromosome]]s.<ref name=pmid-18938248>{{cite journal | vauthors = Delecluse HJ, Feederle R, Behrends U, Mautner J | date = December 2008 | title = Contribution of viral recombinants to the study of the immune response against the Epstein–Barr virus | journal = [[Seminars in Cancer Biology]] | volume = 18 | issue = 6 | pages = 409–415 | pmid = 18938248 | doi = 10.1016/j.semcancer.2008.09.001 }}</ref> Epstein–Barr virus can be maintained and manipulated in the laboratory in continual latency (a property shared with [[Kaposi's sarcoma-associated herpesvirus]], another of the eight human herpesviruses). Although many viruses are assumed to have this property during infection of their natural hosts, there is not an easily managed system for studying this part of the viral lifecycle.  Genomic studies of EBV have been able to explore lytic reactivation and regulation of the latent viral episome.<ref name=pmid-22901543>{{cite journal | vauthors = Arvey A, Tempera I, Tsai K, Chen HS, Tikhmyanova N, Klichinsky M, Leslie C, Lieberman PM | date = August 2012 | title = An atlas of the Epstein–Barr virus transcriptome and epigenome reveals host-virus regulatory interactions | journal = [[Cell Host & Microbe]] | volume = 12 | issue = 2 | pages = 233–245 | pmid = 22901543 | pmc = 3424516 | doi = 10.1016/j.chom.2012.06.008 }}</ref>
Although under active research, an [[Epstein–Barr virus vaccine]] is not yet available. The development of an effective vaccine could prevent up to 200,000&nbsp;cancers globally per year.<ref name=Cancer-Research-UK-200000/><ref name=":0" /> The absence of effective animal models is an obstacle to development of prophylactic and therapeutic vaccines against EBV.<ref name=pmid-34239514>{{cite journal | vauthors=Jean-Pierre V, Lupo J, Germi R | year=2021 | title=Main Targets of Interest for the Development of a Prophylactic or Therapeutic Epstein–Barr Virus Vaccine | journal=[[Frontiers in Microbiology]] | volume=12 | page=701611 | doi = 10.3389/fmicb.2021.701611 | doi-access=free | pmc=8258399 | pmid=34239514 }}</ref>
Like other [[human herpesvirus]]es Epstein–Barr might allow its own eradication via a course of the drug [[valaciclovir]], but further research is needed to determine if eradication is actually achievable.<ref name=pmid-19740997>{{cite journal | vauthors = Hoshino Y, Katano H, Zou P, Hohman P, Marques A, Tyring SK, Follmann D, Cohen JI | date = November 2009 | title = Long-term administration of valacyclovir reduces the number of Epstein–Barr virus (EBV)-infected B&nbsp;cells but not the number of EBV DNA copies per B&nbsp;cell in healthy volunteers | journal = [[Journal of Virology]] | volume = 83 | issue = 22 | pages = 11857–11861 | pmid = 19740997 | pmc = 2772668 | doi = 10.1128/JVI.01005-09 }}</ref> Antiviral agents act by inhibiting viral DNA replication, but there is little evidence that they are effective against Epstein–Barr virus. Moreover, they are expensive, risk causing resistance to antiviral agents, and (in 1% to 10% of cases) can cause unpleasant [[side effect]]s.<ref name=pmid-27933614>{{cite journal | vauthors=de Paor M, O'Brien K, Smith SM | year=2016 | title=Antiviral agents for infectious mononucleosis (glandular fever) | journal=[[Cochrane Library#The Cochrane Database of Systematic Reviews|The Cochrane Database of Systematic Reviews]] | volume=2016 | issue=12 | page=CD011487 | doi = 10.1002/14651858.CD011487.pub2 | pmc=6463965 | pmid=27933614}}</ref>
== See also ==
{{Portal|Medicine|Viruses}}
* [[Epstein–Barr virus infection]]
* [[Epstein–Barr virus-associated lymphoproliferative diseases]]
* [[James Corson Niederman]], the physician who proved how the Epstein–Barr virus is transmitted in infectious mononucleosis
== References ==
{{reflist|25em}}
==Further reading==
* {{Cite magazine |vauthors=Zhang S |date=3 Mar 2022 |title=The puzzling virus that infects almost everyone |magazine=[[The Atlantic (magazine)|The Atlantic]] |url=https://www.theatlantic.com/science/archive/2022/03/epstein-barr-virus-mono-cancer-research/623881/}}
== External links ==
{{Commons category}}
{{Wikispecies}}
* {{Cite web |title=Transcriptome and epigenome of EBV |url=http://ebv.wistar.upenn.edu/ |archive-url=https://web.archive.org/web/20190118154758/https://ebv.wistar.upenn.edu/ |publisher=[[University of Pennsylvania]] |archive-date=18 January 2019 }}
{{Herpesvirales}}
{{Viral diseases}}
{{Taxonbar|from=Q24808752|from2=Q6900}}
[[Category:Epstein–Barr virus| ]]
[[Category:Gammaherpesvirinae| ]]
[[Category:Betaherpesvirinae]]
[[Category:IARC Group 1 carcinogens]]
[[Category:Infectious causes of cancer]]
[[Category:Viral diseases]]