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Chapter 25 : Epstein-Barr Virus

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Epstein-Barr Virus, Page 1 of 2

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Abstract:

In the century preceding the discovery of Epstein-Barr virus (EBV), physicians speculated that a common clinical syndrome characterized by fever, tonsillar adenopathy, splenomegaly, and mononuclear leukocytosis termed glandular fever was caused by a pathogen (1). In 1920, the name infectious mononucleosis (IM) was introduced by Thomas P. Sprunt and Frank A. Evans to characterize this syndrome (2). Three years later, Hal Downey and C.A. McKinlay described the now-classic atypical lymphocyte as a common feature of this disease (3), and in 1932 John Rodman Paul and Walls Willard Bunnell demonstrated high titers of spontaneously occurring heterophile antibodies in the sera of patients with IM (4), ensuring more accurate diagnosis. In 1961, the British surgeon Denis P. Burkitt gave the first account outside of Africa of “The Commonest Children's Cancer in Tropical Africa” at Middlesex Hospital London, detailing the geographic relationship between Burkitt's lymphoma (BL) and conditions of temperature, altitude, and rainfall associated with development of malaria (5, 6). M. Anthony Epstein, who was in the audience, became intrigued by the idea that a biological agent might be involved in the etiology of BL, and in 1964, the Epstein laboratory analyzed BL biopsy samples by thin-section electron microscopy and discovered a new, large, icosahedral herpesvirus that could be directly reactivated from –grown BL cells (7). These initial findings were reported in and the virus was named after Epstein and his graduate student Yvonne Barr (8). Shortly thereafter, two independent groups (9, 10) demonstrated the ability of EBV to transform primary human B lymphocytes into permanently growing lymphoblastoid cell lines (LCLs), providing the first concrete evidence of the ability of EBV to promote human cancer. In 1968, Gertrude Henle and Werner Henle made two further critical observations: (1) that EBV seroconversion occurred during the course of acute IM (AIM) in a laboratory technician (9) and (2) that EBV-carrying LCLs spontaneously formed from a peripheral blood leukocyte culture obtained during the acute phase of the technician's illness. The Henles confirmed their observations through study of sera provided by James Corson Niederman and Robert W. McCollum, who collected blood from incoming Yale freshmen and later from individuals who developed AIM. This study and others demonstrated EBV-specific antibodies in the sera of the students who developed AIM, confirming the etiologic association between EBV and AIM (11).

Citation: Fingeroth J. 2017. Epstein-Barr Virus, p 523-547. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch25
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Image of FIGURE 1
FIGURE 1

Virion composition and genome organization. (a) Electron micrograph of Epstein-Barr virus (EBV) budding from the plasma membrane (). Diagram of virion components (). (b) Diagram of circular genome (episome) with localization of latent transcripts. (c) Diagram of linear genome displaying localization of BamHI fragments. (Modified from ref. with permission; virion image from Wikipedia.)

Citation: Fingeroth J. 2017. Epstein-Barr Virus, p 523-547. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch25
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Image of FIGURE 2
FIGURE 2

Following primary infection, Epstein-Barr virus (EBV) in a latent state accompanies its B cell host through the B lymphocyte maturation process, only switching to the lytic cycle and virus production upon plasma cell (terminal) differentiation. (Diagram of B cell differentiation from Quizlet.com and modified by the author to reflect virus biology.)

Citation: Fingeroth J. 2017. Epstein-Barr Virus, p 523-547. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch25
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Image of FIGURE 3
FIGURE 3

Distinct Epstein-Barr virus (EBV) expression programs (latency III, II, I, 0, lytic replication, abortive replication) are linked with defined stages of B lymphocyte maturation. These same latency patterns are detected in the B cell tumors that arise from transformed cells blocked from further differentiation. Major classes of B cell cancers are indicated in bold. Other EBV-associated tumors that share the indicated latency program but are not of B cell origin are shown in plain font.

Citation: Fingeroth J. 2017. Epstein-Barr Virus, p 523-547. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch25
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Image of FIGURE 4
FIGURE 4

Genomic origin of noncoding RNAs including EBV-encoded RNAs (EBERs), microRNAs (miRNAs), BamHI-A rightward (BART), and an Epstein-Barr virus (EBV) small nucleolar RNA (snoRNA). There is clustering of precursor miRNAs in the BART and to a lesser degree in the BHRF1 region of the genome. (Reproduced from ref. with permission from the journal.)

Citation: Fingeroth J. 2017. Epstein-Barr Virus, p 523-547. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch25
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Image of FIGURE 5
FIGURE 5

Immunobiology of Epstein-Barr virus (EBV) infection in the normal host. Diagram illustrating the transmission, primary infection, persistent infection, and how the cellular immune response becomes activated to prevent disease. (Reproduced from ref. with permission from the journal.)

Citation: Fingeroth J. 2017. Epstein-Barr Virus, p 523-547. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch25
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Image of FIGURE 6
FIGURE 6

Classic Epstein-Barr virus (EBV) serologic responses in acute versus remote versus reactivated EBV infection. (Reproduced from ref. with permission from the journal.)

Citation: Fingeroth J. 2017. Epstein-Barr Virus, p 523-547. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch25
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Image of FIGURE 7
FIGURE 7

Frequency and distribution of CD4 and CD8 T cells in response to lytic and latent cycle Epstein-Barr virus (EBV) proteins. (Reproduced from ref. with permission from the journal.)

Citation: Fingeroth J. 2017. Epstein-Barr Virus, p 523-547. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch25
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Image of FIGURE 8
FIGURE 8

Acute infectious mononucleosis (AIM). Swollen lymph nodes, pharyngitis, fatigue, and headache comprise the four classic symptoms of AIM (). Pharyngitis is often exudative (), and atypical lymphocytes are present in blood (). (Image of symptoms of AIM https://www.nim.nih.gov//medlineplus/ency/imagepages/17267. Image of atypical lymphocytes from Wikipedia; image of pharyngitis from ref. reproduced with permission from the publisher.)

Citation: Fingeroth J. 2017. Epstein-Barr Virus, p 523-547. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch25
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References

/content/book/10.1128/9781555819439.ch25
1. Graser F. 1991. Hundert jahre pfeiffersches drüsenfieber [Glandular fever—100 years of documentation]. Klin Padiatr 203:187190.[PubMed]
2. Sprunt TP, Evans F. 1920. Mononuclear leucocytosis in reaction to acute infections (“infectious mononucleosis”). Bull Johns Hopkins Hosp 31:410.
3. Downey H, McKinlay C. 1923. Acute lymphadenosis compared with acute lymphatic leukemia. Arch Intern Med (Chic) 32:82112.
4. Paul JR, Bunnell WW. 1932. The presence of heterophile antibodies in infectious mononucleosis. Am J Med Sci 183:90103[PubMed].
5. Burkitt D. 1962. A children's cancer dependent on climatic factors. Nature 194:232234.[PubMed]
6. Burkitt DP. 1969. Etiology of Burkitt's lymphoma—an alternative hypothesis to a vectored virus. J Natl Cancer Inst 42:1928.[PubMed]
7. Epstein MA,. 2005. The origins of EBV research: discovery and characterization of the virus, p 114. In Robertson ES (ed), Epstein-Barr Virus. Caister Academic Press, Wymondham, UK.
8. Epstein MA, Achong BG, Barr YM. 1964. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet 283:702703.[PubMed]
9. Henle G, Henle W, Diehl V. 1968. Relation of Burkitt's tumor-associated herpes-type virus to infectious mononucleosis. Proc Natl Acad Sci USA 59:94101.[PubMed]
10. Pope JH. 1968. Establishment of cell lines from Australian leukaemic patients: presence of a herpes-like virus. Aust J Exp Biol Med Sci 46:643645.[PubMed]
11. Niederman JC, McCollum RW, Henle G, Henle W. 1968. Infectious mononucleosis: clinical manifestations in relation to EB virus antibodies. JAMA 203:205209.[PubMed]
12. Kieff E, Rickinson A,. 2007. Epstein-Barr virus and its replication, p 26042634. In Knipe DM, Howley PM, Griffin DE, Lamb RA, Martin MA, Roizman B, Straus SE (ed), Fields Virology. Lippincott Williams & Wilkins, Philadelphia, PA.
13. Dambaugh T, Hennessy K, Chamnankit L, Kieff E. 1984. U2 region of Epstein-Barr virus DNA may encode Epstein-Barr nuclear antigen 2. Proc Natl Acad Sci USA 81:76327636.[PubMed]
14. Baer R, Bankier AT, Biggin MD, Deininger PL, Farrell PJ, Gibson TJ, Hatfull G, Hudson GS, Satchwell SC, Séguin C, Tuffnell PS, Barrell BG. 1984. DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature 310:207211.[PubMed]
15. Zimber U, Adldinger HK, Lenoir GM, Vuillaume M, Knebel-Doeberitz MV, Laux G, Des`granges C, Wittmann P, Freese U-K, Schneider U, Bornkamm GW. 1986. Geographical prevalence of two types of Epstein-Barr virus. Virology 154:5666.[PubMed]
16. Cohen JI, Picchio GR, Mosier DE. 1992. Epstein-Barr virus nuclear protein 2 is a critical determinant for tumor growth in SCID mice and for transformation in vitro. J Virol 66:75557559.[PubMed]
17. Farrell PJ. 2015. Epstein-Barr virus strain variation. Curr Top Microbiol Immunol 390:4569.[PubMed]
18. Edwards RH, Sitki-Green D, Moore DT, Raab-Traub N. 2004. Potential selection of LMP1 variants in nasopharyngeal carcinoma. J Virol 78:868881.[PubMed]
19. White RE, Rämer PC, Naresh KN, Meixlsperger S, Pinaud L, Rooney C, Savoldo B, Coutinho R, Bödör C, Gribben J, Ibrahim HA, Bower M, Nourse JP, Gandhi MK, Middeldorp J, Cader FZ, Murray P, Münz C, Allday MJ. 2012. EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors. J Clin Invest 122:14871502.[PubMed]
20. Kelly GL, Long HM, Stylianou J, Thomas WA, Leese A, Bell AI, Bornkamm GW, Mautner J, Rickinson AB, Rowe M. 2009. An Epstein-Barr virus anti-apoptotic protein constitutively expressed in transformed cells and implicated in Burkitt lymphomagenesis: the Wp/BHRF1 link. PLoS Pathog 5:e1000341.[PubMed]
21. He P, Wu W, Wang HD, Liao KL, Zhang W, Lv FL, Yang K. 2014. Why ligand cross-reactivity is high within peptide recognition domain families? A case study on human c-Src SH3 domain. J Theor Biol 340:3037.[PubMed]
22. Tzellos S, Farrell PJ. 2012. Epstein-Barr virus sequence variation—biology and disease. Pathogens 1:156174.[PubMed]
23. Feederle R, Klinke O, Kutikhin A, Poirey R, Tsai MH, Delecluse HJ. 2015. Epstein-Barr virus: from the detection of sequence polymorphisms to the recognition of viral yypes. Curr Top Microbiol Immunol 390:119148.[PubMed]
24. Johannsen E, Luftig M, Chase MR, Weicksel S, Cahir-McFarland E, Illanes D, Sarracino D, Kieff E. 2004. Proteins of purified Epstein-Barr virus. Proc Natl Acad Sci USA 101:1628616291.[PubMed]
25. Lindner SE, Sugden B. 2007. The plasmid replicon of Epstein-Barr virus: mechanistic insights into efficient, licensed, extrachromosomal replication in human cells. Plasmid 58:112.[PubMed]
26. Raab-Traub N, Flynn K. 1986. The structure of the termini of the Epstein-Barr virus as a marker of clonal cellular proliferation. Cell 47:883889.[PubMed]
27. Packham G, Economou A, Rooney CM, Rowe DT, Farrell PJ. 1990. Structure and function of the Epstein-Barr virus BZLF1 protein. J Virol 64:21102116.[PubMed]
28. Cleary ML, Smith SD, Sklar J. 1986. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 47:1928.[PubMed]
29. Strockbine LD, Cohen JI, Farrah T, Lyman SD, Wagener F, DuBose RF, Armitage RJ, Spriggs MK. 1998. The Epstein-Barr virus BARF1 gene encodes a novel, soluble colony-stimulating factor-1 receptor. J Virol 72:40154021.[PubMed]
30. Pfeffer S, Zavolan M, Grässer FA, Chien M, Russo JJ, Ju J, John B, Enright AJ, Marks D, Sander C, Tuschl T. 2004. Identification of virus-encoded microRNAs. Science 304:734736.[PubMed]
31. Skalsky RL, Cullen BR. 2015. EBV noncoding RNAs. Curr Top Microbiol Immunol 391:181217.[PubMed]
32. Ehlers B, Spiess K, Leendertz F, Peeters M, Boesch C, Gatherer D, McGeoch DJ. 2010. Lymphocryptovirus phylogeny and the origins of Epstein-Barr virus. J Gen Virol 91:630642.[PubMed]
33. Gerner CS, Dolan A, McGeoch DJ. 2004. Phylogenetic relationships in the Lymphocryptovirus genus of the Gammaherpesvirinae. Virus Res 99:187192.[PubMed]
34. Mühe J, Wang F. 2015. Non-human primate lymphocryptoviruses: past, present, and future. Curr Top Microbiol Immunol 391:385405.[PubMed]
35. Miller G, Shope T, Lisco H, Stitt D, Lipman M. 1972. Epstein-Barr virus: transformation, cytopathic changes, and viral antigens in squirrel monkey and marmoset leukocytes. Proc Natl Acad Sci USA 69:383387.[PubMed]
36. Epstein MA. 1976. EB virus in the owl monkey (Aotus trivirgatus). Lab Anim Sci 26:11271130.[PubMed]
37. Mühe J, Wang F. 2015. Host range restriction of Epstein-Barr virus and related lymphocryptoviruses. J Virol 89:91339136.[PubMed]
38. Yajima M, Imadome K, Nakagawa A, Watanabe S, Terashima K, Nakamura H, Ito M, Shimizu N, Honda M, Yamamoto N, Fujiwara S. 2008. A new humanized mouse model of Epstein-Barr virus infection that reproduces persistent infection, lymphoproliferative disorder, and cell-mediated and humoral immune responses. J Infect Dis 198:673682.[PubMed]
39. Boisgontier MP. 2015. Motor aging results from cerebellar neuron death. Trends Neurosci 38:127128.[PubMed]
40. Münz C. 2015. EBV infection of mice with reconstituted human immune system components. Curr Top Microbiol Immunol 391:407423.[PubMed]
41. Fingeroth JD, Weis JJ, Tedder TF, Strominger JL, Biro PA, Fearon DT. 1984. Epstein-Barr virus receptor of human B lymphocytes is the C3d receptor CR2. Proc Natl Acad Sci USA 81:45104514.[PubMed]
42. Cooper NR, Moore MD, Nemerow GR. 1988. Immunobiology of CR2, the B lymphocyte receptor for Epstein-Barr virus and the C3d complement fragment. Annu Rev Immunol 6:85113.[PubMed]
43. Tanner J, Weis J, Fearon D, Whang Y, Kieff E. 1987. Epstein-Barr virus gp350/220 binding to the B lymphocyte C3d receptor mediates adsorption, capping, and endocytosis. Cell 50:203213.[PubMed]
44. Nemerow GR, Houghten RA, Moore MD, Cooper NR. 1989. Identification of an epitope in the major envelope protein of Epstein-Barr virus that mediates viral binding to the B lymphocyte EBV receptor (CR2). Cell 56:369377.[PubMed]
45. Calattini S, Sereti I, Scheinberg P, Kimura H, Childs RW, Cohen JI. 2010. Detection of EBV genomes in plasmablasts/plasma cells and non-B cells in the blood of most patients with EBV lymphoproliferative disorders by using Immuno-FISH. Blood 116:45464559.[PubMed]
46. Tsoukas CD, Lambris JD. 1993. Expression of EBV/C3d receptors on T cells: biological significance. Immunol Today 14:5659.[PubMed]
47. Ogembo JG, Kannan L, Ghiran I, Nicholson-Weller A, Finberg RW, Tsokos GC, Fingeroth JD. 2013. Human complement receptor type 1/CD35 is an Epstein-Barr virus receptor. Cell Reports 3:371385.[PubMed]
48. Jiang R, Gu X, Moore-Medlin TN, Nathan CA, Hutt-Fletcher LM. 2012. Oral dysplasia and squamous cell carcinoma: correlation between increased expression of CD21, Epstein-Barr virus and CK19. Oral Oncol 48:836841.[PubMed]
49. Fingeroth JD, Diamond ME, Sage DR, Hayman J, Yates JL. 1999. CD21-dependent infection of an epithelial cell line, 293, by Epstein-Barr virus. J Virol 73:21152125.[PubMed]
50. Luxembourg AT, Cooper NR. 1994. Modulation of signaling via the B cell antigen receptor by CD21, the receptor for C3dg and EBV. J Immunol 153:44484457.[PubMed]
51. Sugano N, Chen W, Roberts ML, Cooper NR. 1997. Epstein-Barr virus binding to CD21 activates the initial viral promoter via NF-kappaB induction. J Exp Med 186:731737.[PubMed]
52. Arredouani MS, Bhasin MK, Sage DR, Dunn LK, Gill MB, Agnani D, Libermann TA, Fingeroth JD. 2014. Analysis of host gene expression changes reveals distinct roles for the cytoplasmic domain of the Epstein-Barr virus receptor/CD21 in B-cell maturation, activation, and initiation of virus infection. J Virol 88:55595577.[PubMed]
53. Krummenacher C, Carfí A, Eisenberg RJ, Cohen GH. 2013. Entry of herpesviruses into cells: the enigma variations. Adv Exp Med Biol 790:178195.[PubMed]
54. Hutt-Fletcher LM. 2007. Epstein-Barr virus entry. J Virol 81:78257832.[PubMed]
55. Garcia NJ, Chen J, Longnecker R. 2013. Modulation of Epstein-Barr virus glycoprotein B (gB) fusion activity by the gB cytoplasmic tail domain. MBio 4:e00571-12.[PubMed]
56. Temple RM, Zhu J, Budgeon L, Christensen ND, Meyers C, Sample CE. 2014. Efficient replication of Epstein-Barr virus in stratified epithelium in vitro. Proc Natl Acad Sci USA 111:1654416549.[PubMed]
57. Nawandar DM, Wang A, Makielski K, Lee D, Ma S, Barlow E, Reusch J, Jiang R, Wille CK, Greenspan D, Greenspan JS, Mertz JE, Hutt-Fletcher L, Johannsen EC, Lambert PF, Kenney SC. 2015. Differentiation-dependent KLF4 expression promotes lytic Epstein-Barr virus infection in epithelial cells. PLoS Pathog 11:e1005195.[PubMed]
58. Shannon-Lowe CD, Neuhierl B, Baldwin G, Rickinson AB, Delecluse HJ. 2006. Resting B cells as a transfer vehicle for Epstein-Barr virus infection of epithelial cells. Proc Natl Acad Sci USA 103:70657070.[PubMed]
59. Faulkner GC, Burrows SR, Khanna R, Moss DJ, Bird AG, Crawford DH. 1999. X-linked agammaglobulinemia patients are not infected with Epstein-Barr virus: implications for the biology of the virus. J Virol 73:15551564.[PubMed]
60. Gratama JW, Oosterveer MA, Zwaan FE, Lepoutre J, Klein G, Ernberg I. 1988. Eradication of Epstein-Barr virus by allogeneic bone marrow transplantation: implications for sites of viral latency. Proc Natl Acad Sci USA 85:86938696.[PubMed]
61. Turk SM, Jiang R, Chesnokova LS, Hutt-Fletcher LM. 2006. Antibodies to gp350/220 enhance the ability of Epstein-Barr virus to infect epithelial cells. J Virol 80:96289633.[PubMed]
62. Borza CM, Hutt-Fletcher LM. 2002. Alternate replication in B cells and epithelial cells switches tropism of Epstein-Barr virus. Nat Med 8:594599.[PubMed]
63. Chesnokova LS, Hutt-Fletcher LM. 2014. Epstein-Barr virus infection mechanisms. Chin J Cancer 33:545548.[PubMed]
64. Chesnokova LS, Jiang R, Hutt-Fletcher LM. 2015. Viral entry. Curr Top Microbiol Immunol 391:221235.[PubMed]
65. Valencia SM, Hutt-Fletcher LM. 2012. Important but differential roles for actin in trafficking of Epstein-Barr virus in B cells and epithelial cells. J Virol 86:210.[PubMed]
66. Heilmann AM, Calderwood MA, Johannsen E. 2010. Epstein-Barr virus LF2 protein regulates viral replication by altering Rta subcellular localization. J Virol 84:99209931.[PubMed]
67. Tempera I, Lieberman PM. 2014. Epigenetic regulation of EBV persistence and oncogenesis. Semin Cancer Biol 26:2229[PubMed]
68. Lieberman PM. 2015. Chromatin structure of Epstein-Barr virus latent episomes. Curr Top Microbiol Immunol 390:71102.[PubMed]
69. Wille CK, Nawandar DM, Henning AN, Ma S, Oetting KM, Lee D, Lambert P, Johannsen EC, Kenney SC. 2015. 5-hydroxymethylation of the EBV genome regulates the latent to lytic switch. Proc Natl Acad Sci USA 112:E7257E7265.[PubMed]
70. Hammerschmidt W, Sugden B. 2013. Replication of Epstein-Barr viral DNA. Cold Spring Harb Perspect Biol 5:a013029.[PubMed]
71. Speck SH, Chatila T, Flemington E. 1997. Reactivation of Epstein-Barr virus: regulation and function of the BZLF1 gene. Trends Microbiol 5:399405.[PubMed]
72. Kenney SC, Mertz JE. 2014. Regulation of the latent-lytic switch in Epstein-Barr virus. Semin Cancer Biol 26:6068.[PubMed]
73. Murata T, Tsurumi T. 2014. Switching of EBV cycles between latent and lytic states. Rev Med Virol 24:142153.[PubMed]
74. Howe JG, Shu MD. 1989. Epstein-Barr virus small RNA (EBER) genes: unique transcription units that combine RNA polymerase II and III promoter elements. Cell 57:825834.[PubMed]
75. McClellan MJ, Wood CD, Ojeniyi O, Cooper TJ, Kanhere A, Arvey A, Webb HM, Palermo RD, Harth-Hertle ML, Kempkes B, Jenner RG, West MJ. 2013. Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming. PLoS Pathog 9:e1003636.[PubMed]
76. Kempkes B, Robertson ES. 2015. Epstein-Barr virus latency: current and future perspectives. Curr Opin Virol 14:138144.[PubMed]
77. Price AM, Tourigny JP, Forte E, Salinas RE, Dave SS, Luftig MA. 2012. Analysis of Epstein–Barr virus–regulated host gene expression changes through primary B-cell outgrowth reveals delayed kinetics of latent membrane protein 1-mediated NF-κB activation. J Virol 86:1109611106.[PubMed]
78. Kang MS, Kieff E. 2015. Epstein-Barr virus latent genes. Exp Mol Med 47:e131.[PubMed]
79. Frappier L. 2015. Ebna1. Curr Top Microbiol Immunol 391:334.[PubMed]
80. Hodin TL, Najrana T, Yates JL. 2013. Efficient replication of Epstein-Barr virus–derived plasmids requires tethering by EBNA1 to host chromosomes. J Virol 87:1302013028.[PubMed]
81. Kempkes B, Ling PD. 2015. EBNA2 and its coactivator EBNA-LP. Curr Top Microbiol Immunol 391:3559.[PubMed]
82. Tomkinson B, Robertson E, Kieff E. 1993. Epstein-Barr virus nuclear proteins EBNA-3A and EBNA-3C are essential for B-lymphocyte growth transformation. J Virol 67:20142025.[PubMed]
83. Allday MJ, Bazot Q, White RE. 2015. The EBNA3 family: two oncoproteins and a tumour suppressor that are central to the biology of EBV in B cells. Curr Top Microbiol Immunol 391:61117.[PubMed]
84. Longnecker RM, Kieff R, Cohen JI,. 2013. Epstein-Barr virus, p 18981959. In Fields BN, Knipe DM, Howley PM (ed), Fields Virology. Wolters Kluwer Health/Lippincott Williams & Wilkins, Philadelphia.
85. Stunz LL, Bishop GA. 2014. Latent membrane protein 1 and the B lymphocyte-a complex relationship. Crit Rev Immunol 34:177198.[PubMed]
86. Kieser A, Sterz KR. 2015. The latent membrane protein 1 (LMP1). Curr Top Microbiol Immunol 391:119149.[PubMed]
87. Izumi KM, Kaye KM, Kieff ED. 1997. The Epstein-Barr virus LMP1 amino acid sequence that engages tumor necrosis factor receptor associated factors is critical for primary B lymphocyte growth transformation. Proc Natl Acad Sci USA 94:14471452.[PubMed]
88. Caldwell RG, Wilson JB, Anderson SJ, Longnecker R. 1998. Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity 9:405411.[PubMed]
89. Cen O, Longnecker R. 2015. Latent membrane protein 2 (LMP2). Curr Top Microbiol Immunol 391:151180.[PubMed]
90. Dawson CW, Port RJ, Young LS. 2012. The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). Semin Cancer Biol 22:144153.[PubMed]
91. Swaminathan S, Tomkinson B, Kieff E. 1991. Recombinant Epstein-Barr virus with small RNA (EBER) genes deleted transforms lymphocytes and replicates in vitro. Proc Natl Acad Sci USA 88:15461550.[PubMed]
92. Samanta M, Takada K. 2010. Modulation of innate immunity system by Epstein–Barr virus–encoded non-coding RNA and oncogenesis. Cancer Sci 101:2935.[PubMed]
93. Moss WN, Lee N, Pimienta G, Steitz JA. 2014. RNA families in Epstein-Barr virus. RNA Biol 11:1017.[PubMed]
94. Marquitz AR, Mathur A, Edwards RH, Raab-Traub N. 2015. Host gene expression is regulated by two types of noncoding RNAs transcribed from the Epstein-Barr virus BamHI A rightward transcript region. J Virol 89:1125611268.[PubMed]
95. Bernhardt K, Haar J, Tsai MH, Poirey R, Feederle R, Delecluse HJ. 2016. A viral microRNA cluster regulates the expression of PTEN, p27 and of a bcl-2 homolog. PLoS Pathog 12:e1005405.[PubMed]
96. Thorley-Lawson DA. 2015. EBV persistence—introducing the virus. Curr Top Microbiol Immunol 390:151209.[PubMed]
97. Hochberg D, Souza T, Catalina M, Sullivan JL, Luzuriaga K, Thorley-Lawson DA. 2004. Acute infection with Epstein-Barr virus targets and overwhelms the peripheral memory B-cell compartment with resting, latently infected cells. J Virol 78:51945204.[PubMed]
98. Laichalk LL, Thorley-Lawson DA. 2005. Terminal differentiation into plasma cells initiates the replicative cycle of Epstein-Barr virus in vivo. J Virol 79:12961307.[PubMed]
99. Hadinoto V, Shapiro M, Greenough TC, Sullivan JL, Luzuriaga K, Thorley-Lawson DA. 2008. On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis. Blood 111:14201427.[PubMed]
100. Hammerschmidt W. 2015. The epigenetic life cycle of Epstein-Barr virus. Curr Top Microbiol Immunol 390:103117.[PubMed]
101. McKenzie J, El-Guindy A. 2015. Epstein-Barr virus lytic cycle reactivation. Curr Top Microbiol Immunol 391:237261.[PubMed]
102. Zheng X, Wu C, Liu D, Li H, Bitan G, Shea JE, Bowers MT. 2016. Mechanism of C-terminal fragments of amyloid β-protein as Aβ inhibitors: do C-terminal interactions play a key role in their inhibitory activity? J Phys Chem B 120:16151623.[PubMed]
103. Williams LR, Quinn LL, Rowe M, Zuo J. 2016. Induction of the lytic cycle sensitizes Epstein-Barr virus–infected B cells to NK cell killing that is counteracted by virus-mediated NK cell evasion mechanisms in the late lytic cycle. J Virol 90:947958.[PubMed]
104. Biggar RJ, Henle W, Fleisher G, Böcker J, Lennette ET, Henle G. 1978. Primary Epstein-Barr virus infections in African infants. I. Decline of maternal antibodies and time of infection. Int J Cancer 22:239243.[PubMed]
105. Biggar RJ, Henle G, Böcker J, Lennette ET, Fleisher G, Henle W. 1978. Primary Epstein-Barr virus infections in African infants. II. Clinical and serological observations during seroconversion. Int J Cancer 22:244250.[PubMed]
106. Luzuriaga K, Sullivan JL. 2010. Infectious mononucleosis. N Engl J Med 362:19932000.[PubMed]
107. Hjalgrim H, Friborg J, Melbye M,. 2007. The epidemiology of EBV and its association with malignant disease, p 929959. In Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, Whitley R, Yamanishi K (ed), Human Herpesviruses: Biology. Therapy, and Immunoprophylaxis. Cambridge.
108. Hjalgrim H. 2012. On the aetiology of Hodgkin lymphoma. Dan Med J 59:B4485.[PubMed]
109. Crawford DH, Macsween KF, Higgins CD, Thomas R, McAulay K, Williams H, Harrison N, Reid S, Conacher M, Douglas J, Swerdlow AJ. 2006. A cohort study among university students: identification of risk factors for Epstein-Barr virus seroconversion and infectious mononucleosis. Clin Infect Dis 43:276282.[PubMed]
110. Balfour HH Jr, Odumade OA, Schmeling DO, Mullan BD, Ed JA, Knight JA, Vezina HE, Thomas W, Hogquist KA. 2013. Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein-Barr virus infection in university students. J Infect Dis 207:8088.[PubMed]
111. Balfour HH Jr, Dunmire SK, Hogquist KA. 2015. Infectious mononucleosis. Clin Transl Immunology 4:e33.[PubMed]
112. Hjalgrim H, Seow A, Rostgaard K, Friborg J. 2008. Changing patterns of Hodgkin lymphoma incidence in Singapore. Int J Cancer 123:716719.[PubMed]
113. Daud II, Coleman CB, Smith NA, Ogolla S, Simbiri K, Bukusi EA, Ng'ang'a ZW, Sumba PO, Vulule J, Ploutz-Snyder R, Dent AE, Rochford R. 2015. Breast milk as a potential source of Epstein-Barr virus transmission among infants living in a malaria-endemic region of Kenya. J Infect Dis 212:17351742.[PubMed]
114. Fleisher GR, Pasquariello PS, Warren WS, Zavod WS, Korval AB, Turner HD, Lennette ET. 1981. Intrafamilial transmission of Epstein-Barr virus infections. J Pediatr 98:1619.[PubMed]
115. Chang RS, Rosen L, Kapikian AZ. 1981. Epstein-Barr virus infections in a nursery. Am J Epidemiol 113:2229.[PubMed]
116. Sixbey JW, Lemon SM, Pagano JS. 1986. A second site for Epstein-Barr virus shedding: the uterine cervix. Lancet 328:11221124.[PubMed]
117. Le CT, Chang RS, Lipson MH. 1983. Epstein-Barr virus infections during pregnancy. A prospective study and review of the literature. Am J Dis Child 137:466468.[PubMed]
118. Balfour HH Jr, Holman CJ, Hokanson KM, Lelonek MM, Giesbrecht JE, White DR, Schmeling DO, Webb CH, Cavert W, Wang DH, Brundage RC. 2005. A prospective clinical study of Epstein-Barr virus and host interactions during acute infectious mononucleosis. J Infect Dis 192:15051512.[PubMed]
119. Schooley RT,. 2001. Principles and practice of infectious diseases, p 1601. In Mandell GL, Bennett JE, Dolin R (ed), Principles and Practice of Infectious Diseases. Churchill Livingstone, New York.
120. Anagnostopoulos I, Hummel M, Kreschel C, Stein H. 1995. Morphology, immunophenotype, and distribution of latently and/or productively Epstein-Barr virus-infected cells in acute infectious mononucleosis: implications for the interindividual infection route of Epstein-Barr virus. Blood 85:744750.[PubMed]
121. Karajannis MA, Hummel M, Anagnostopoulos I, Stein H. 1997. Strict lymphotropism of Epstein-Barr virus during acute infectious mononucleosis in nonimmunocompromised individuals. Blood 89:28562862.[PubMed]
122. Kratzmeier M, Albig W, Meergans T, Doenecke D. 1999. Changes in the protein pattern of H1 histones associated with apoptotic DNA fragmentation. Biochem J 337:319327.[PubMed]
123. Dunmire SK, Grimm JM, Schmeling DO, Balfour HH Jr, Hogquist KA. 2015. The incubation period of primary Epstein-Barr virus infection: viral dynamics and immunologic events. PLoS Pathog 11:e1005286.[PubMed]
124. Hislop AD. 2015. Early virological and immunological events in Epstein-Barr virus infection. Curr Opin Virol 15:7579.[PubMed]
125. Dunmire SK, Hogquist KA, Balfour HH. 2015. Infectious mononucleosis. Curr Top Microbiol Immunol 390:211240.[PubMed]
126. Middeldorp JM. 2015. Epstein-Barr virus–specific humoral immune responses in health and disease. Curr Top Microbiol Immunol 391:289323.[PubMed]
127. de Ory F, Guisasola E, Tarragó D, Sanz JC. 2015. Application of a commercial immunoblot to define EBV IgG seroprofiles. J Clin Lab Anal 29:4751.[PubMed]
128. Fachiroh J, Schouten T, Hariwiyanto B, Paramita DK, Harijadi A, Haryana SM, Ng MH, Middeldorp JM. 2004. Molecular diversity of Epstein-Barr virus IgG and IgA antibody responses in nasopharyngeal carcinoma: a comparison of Indonesian, Chinese, and European subjects. J Infect Dis 190:5362.[PubMed]
129. Zheng D, Wan J, Cho YG, Wang L, Chiou CJ, Pai S, Woodard C, Zhu J, Liao G, Martinez-Maza O, Qian J, Zhu H, Hayward GS, Ambinder RF, Hayward SD. 2011. Comparison of humoral immune responses to Epstein-Barr virus and Kaposi's sarcoma–associated herpesvirus using a viral proteome microarray. J Infect Dis 204:16831691.[PubMed]
130. Thorley-Lawson DA, Poodry CA. 1982. Identification and isolation of the main component (gp350-gp220) of Epstein-Barr virus responsible for generating neutralizing antibodies in vivo. J Virol 43:730736.[PubMed]
131. North JR, Morgan AJ, Thompson JL, Epstein MA. 1982. Purified Epstein-Barr virus Mr 340,000 glycoprotein induces potent virus-neutralizing antibodies when incorporated in liposomes. Proc Natl Acad Sci USA 79:75047508.[PubMed]
132. Sashihara J, Burbelo PD, Savoldo B, Pierson TC, Cohen JI. 2009. Human antibody titers to Epstein-Barr virus (EBV) gp350 correlate with neutralization of infectivity better than antibody titers to EBV gp42 using a rapid flow cytometry-based EBV neutralization assay. Virology 391:249256.[PubMed]
133. Panikkar A, Smith C, Hislop A, Tellam N, Dasari V, Hogquist KA, Wykes M, Moss DJ, Rickinson A, Balfour HH Jr, Khanna R. 2015. Impaired Epstein-Barr virus-specific neutralizing antibody response during acute infectious mononucleosis is coincident with global B-cell dysfunction. J Virol 89:91379141.[PubMed]
134. Bu W, Hayes GM, Liu H, Gemmell L, Schmeling DO, Radecki P, Aguilar F, Burbelo PD, Woo J, Balfour HH Jr, Cohen JI. 2016. Kinetics of Epstein-Barr virus (EBV) neutralizing and virus-specific antibodies after primary infection with EBV. Clin Vaccine Immunol 23:363369.[PubMed]
135. Khyatti M, Patel PC, Stefanescu I, Menezes J. 1991. Epstein-Barr virus (EBV) glycoprotein gp350 expressed on transfected cells resistant to natural killer cell activity serves as a target antigen for EBV-specific antibody-dependent cellular cytotoxicity. J Virol 65:9961001.[PubMed]
136. Pfuhl C, Oechtering J, Rasche L, Gieß RM, Behrens JR, Wakonig K, Freitag E, Pache FC, Otto C, Hofmann J, Eberspächer B, Bellmann-Strobl J, Paul F, Ruprecht K. 2015. Association of serum Epstein-Barr nuclear antigen-1 antibodies and intrathecal immunoglobulin synthesis in early multiple sclerosis. J Neuroimmunol 285:156160.[PubMed]
137. Draborg A, Izarzugaza JM, Houen G. 2016. How compelling are the data for Epstein-Barr virus being a trigger for systemic lupus and other autoimmune diseases? Curr Opin Rheumatol 28:398404.[PubMed]
138. Masucci MG, Bejarano MT, Masucci G, Klein E. 1983. Large granular lymphocytes inhibit the in vitro growth of autologous Epstein-Barr virus-infected B cells. Cell Immunol 76:311321.[PubMed]
139. Andersson U, Martinez-Maza O, Andersson J, Britton S, Gaoler H, De Ley M, Modrow S. 1984. Secretion of gamma-interferon at the cellular level: induction by Epstein-Barr virus. Scand J Immunol 20:425432[CrossRef].[PubMed]
140. Thorley-Lawson DA. 1981. The transformation of adult but not newborn human lymphocytes by Epstein Barr virus and phytohemagglutinin is inhibited by interferon: the early suppression by T cells of Epstein Barr infection is mediated by interferon. J Immunol 126:829833.[PubMed]
141. Biron CA, Byron KS, Sullivan JL. 1989. Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med 320:17311735.[PubMed]
142. Hendricks DW, Balfour HH Jr, Dunmire SK, Schmeling DO, Hogquist KA, Lanier LL. 2014. Cutting edge: NKG2C(hi)CD57+ NK cells respond specifically to acute infection with cytomegalovirus and not Epstein-Barr virus. J Immunol 192:44924496.[PubMed]
143. Münz C. 2014. Role of human natural killer cells during Epstein-Barr virus infection. Crit Rev Immunol 34:501507.[PubMed]
144. Azzi T, Lünemann A, Murer A, Ueda S, Béziat V, Malmberg KJ, Staubli G, Gysin C, Berger C, Münz C, Chijioke O, Nadal D. 2014. Role for early-differentiated natural killer cells in infectious mononucleosis. Blood 124:25332543.[PubMed]
145. Lünemann A, Rowe M, Nadal D. 2015. Innate immune recognition of EBV. Curr Top Microbiol Immunol 391:265287.[PubMed]
146. Ohashi M, Fogg MH, Orlova N, Quink C, Wang F. 2012. An Epstein-Barr virus encoded inhibitor of Colony Stimulating Factor-1 signaling is an important determinant for acute and persistent EBV infection. PLoS Pathog 8:e1003095.[PubMed]
147. Panikkar A, Smith C, Hislop A, Tellam N, Dasari V, Hogquist KA, Wykes M, Moss DJ, Rickinson A, Balfour HH Jr, Khanna R. 2015. Cytokine-mediated loss of blood dendritic cells during Epstein-Barr virus–associated acute infectious mononucleosis: implication for immune dysregulation. J Infect Dis 212:19571961.[PubMed]
148. Cornberg M, Clute SC, Watkin LB, Saccoccio FM, Kim SK, Naumov YN, Brehm MA, Aslan N, Welsh RM, Selin LK. 2010. CD8 T cell cross-reactivity networks mediate heterologous immunity in human EBV and murine vaccinia virus infections. J Immunol 184:28252838.[PubMed]
149. Moss DJ, Burrows SR, Khanna R,. 2007. EBV: immunobiology and host response, p 904914. In Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, Whitley R, Yamanishi K (ed), Human Herpesviruses: Biology. Therapy, and Immunoprophylaxis, Cambridge.
150. Rickinson AB, Long HM, Palendira U, Münz C, Hislop AD. 2014. Cellular immune controls over Epstein-Barr virus infection: new lessons from the clinic and the laboratory. Trends Immunol 35:159169.[PubMed]
151. Taylor GS, Long HM, Brooks JM, Rickinson AB, Hislop AD. 2015. The immunology of Epstein-Barr virus–induced disease. Annu Rev Immunol 33:787821.[PubMed]
152. Palendira U, Rickinson AB. 2015. Primary immunodeficiencies and the control of Epstein-Barr virus infection. Ann N Y Acad Sci 1356:2244.[PubMed]
153. Cohen JI. 2015. Primary immunodeficiencies associated with EBV disease. Curr Top Microbiol Immunol 390:241265.[PubMed]
154. Doherty PC. 1998. The numbers game for virus-specific CD8+ T cells. Science 280:227.[PubMed]
155. McMichael AJ, O'Callaghan CA. 1998. A new look at T cells. J Exp Med 187:13671371.[PubMed]
156. Smith-Garvin JE, Koretzky GA, Jordan MS. 2009. T cell activation. Annu Rev Immunol 27:591619.[PubMed]
157. Callan MF, Tan L, Annels N, Ogg GS, Wilson JD, O'Callaghan CA, Steven N, McMichael AJ, Rickinson AB. 1998. Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus in vivo. J Exp Med 187:13951402.[PubMed]
158. Catalina MD, Sullivan JL, Bak KR, Luzuriaga K. 2001. Differential evolution and stability of epitope-specific CD8(+) T cell responses in EBV infection. J Immunol 167:44504457.[PubMed]
159. Precopio ML, Sullivan JL, Willard C, Somasundaran M, Luzuriaga K. 2003. Differential kinetics and specificity of EBV-specific CD4+ and CD8+ T cells during primary infection. J Immunol 170:25902598.[PubMed]
160. Goldberg GN, Fulginiti VA, Ray CG, Ferry P, Jones JF, Cross H, Minnich L. 1981. In utero Epstein-Barr virus (infectious mononucleosis) infection. JAMA 246:15791581.[PubMed]
161. Fleisher G, Bologonese R. 1984. Epstein-Barr virus infections in pregnancy: a prospective study. J Pediatr 104:374379.[PubMed]
162. Grose C. 1985. The many faces of infectious mononucleosis: the spectrum of Epstein-Barr virus infection in children. Pediatr Rev 7:3544.
163. Horwitz CA, Henle W, Henle G, Goldfarb M, Kubic P, Gehrz RC, Balfour HH Jr, Fleisher GR, Krivit W. 1981. Clinical and laboratory evaluation of infants and children with Epstein-Barr virus–induced infectious mononucleosis: report of 32 patients (aged 10–48 months). Blood 57:933938.[PubMed]
164. Tamaki H, Beaulieu BL, Somasundaran M, Sullivan JL. 1995. Major histocompatibility complex class I-restricted cytotoxic T lymphocyte responses to Epstein-Barr virus in children. J Infect Dis 172:739746.[PubMed]
165. Hurt C, Tammaro D. 2007. Diagnostic evaluation of mononucleosis-like illnesses. Am J Med 120:911918.
166. Ebell MH, Call M, Shinholser J, Gardner J. 2016. Does this patient have infectious mononucleosis? The Rational Clinical Examination Systematic Review. JAMA 315:15021509.[PubMed]
167. Chang RS. 1980. Infectious mononucleosis. Hall, Boston, MA.
168. Haverkos HW, Amsel Z, Drotman DP. 1991. Adverse virus-drug interactions. Rev Infect Dis 13:697704.[PubMed]
169. Aldrete JS. 1992. Spontaneous rupture of the spleen in patients with infectious mononucleosis. Mayo Clin Proc 67:910912.[PubMed]
170. Bartlett A, Williams R, Hilton M. 2016. Splenic rupture in infectious mononucleosis: a systematic review of published case reports. Injury 47:531538.[PubMed]
171. Rezk E, Nofal YH, Hamzeh A, Aboujaib MF, AlKheder MA, Al Hammad MF. 2015. Steroids for symptom control in infectious mononucleosis. Cochrane Database Syst Rev 11:CD004402.[PubMed]