Skip to main content
SpringerLink
Log in

Epstein-Barr Virus Lytic Cycle Reactivation

  • Chapter
  • First Online:
Epstein Barr Virus Volume 2

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 391))

Abstract

Epstein-Barr virus, which mainly infects B cells and epithelial cells, has two modes of infection: latent and lytic. Epstein-Barr virus infection is predominantly latent; however, lytic infection is detected in healthy seropositive individuals and becomes more prominent in certain pathological conditions. Lytic infection is divided into several stages: early gene expression, DNA replication, late gene expression, assembly, and egress. This chapter summarizes the most recent progress made toward understanding the molecular mechanisms that regulate the different lytic stages leading to production of viral progeny. In addition, the chapter highlights the potential role of lytic infection in disease development and current attempts to purposely induce lytic infection as a therapeutic approach.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ATF:

CAMP-dependent transcription factor

ATM:

Ataxia telangiectasia-mutated

AP-1:

Activator protein-1

BCR:

B cell receptor

BLIMP1:

B lymphocyte-induced maturation protein-1

bZIP:

Basic leucine zipper

CBP:

CREB-binding protein

C/EBP:

CCAAT/enhancer-binding protein

CREB:

CAMP response element-binding protein

EBF1:

Early B cell factor 1

EBV:

Epstein-Barr virus

HAT:

Histone acetyltransferase

HDAC:

Histone deacetylase

HIF:

Hypoxia-inducible factor

IP3:

Inositol triphosphate

JDP2:

Jun dimerization protein

KLF:

Kruppel-like factors

MEF2:

Myocyte enhancer factor 2

MAPK:

Mitogen-activated protein kinase(s)

MCAF1:

MBD1-containing chromatin-associated factor 1

PKC:

Protein kinase C

PI3K:

Phosphoinositide 3-kinase

RNAP:

RNA polymerase

SBE:

SMAD-binding elements

SP:

Specificity protein

TBP:

TATA-binding protein

vIL-10:

Viral homolog of interleukin 10

XBP1:

X-box-binding protein 1

ZEB:

Zinc finger E-box-binding proteins

ZEBRA:

BamHI Z fragment Epstein-Barr virus Replication Activator

ZREs:

ZEBRA response elements

References

  • Adamson AL, Kenney S (1999) The Epstein-Barr virus BZLF1 protein interacts physically and functionally with the histone acetylase CREB-binding protein. J Virol 73:6551–6558

    PubMed Central  CAS  PubMed  Google Scholar 

  • Adamson AL, Darr D, Holley-Guthrie E, Johnson RA, Mauser A, Swenson J, Kenney S (2000) Epstein-Barr virus immediate-early proteins BZLF1 and BRLF1 activate the ATF2 transcription factor by increasing the levels of phosphorylated p38 and c-Jun N-terminal kinases. J Virol 74:1224–1233

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Altmann M, Hammerschmidt W (2005) Epstein-Barr virus provides a new paradigm: a requirement for the immediate inhibition of apoptosis. PLoS Biol 3:e404

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Amon W, Binne UK, Bryant H, Jenkins PJ, Karstegl CE, Farrell PJ (2004) Lytic cycle gene regulation of Epstein-Barr virus. J Virol 78:13460–13469

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Arvey A, Tempera I, Tsai K, Chen HS, Tikhmyanova N, Klichinsky M, Leslie C, Lieberman PM (2012) An atlas of the Epstein-Barr virus transcriptome and epigenome reveals host-virus regulatory interactions. Cell Host Microbe 12:233–245

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Aubry V, Mure F, Mariame B, Deschamps T, Wyrwicz LS, Manet E, Gruffat H (2014) Epstein-barr virus late gene transcription depends on the assembly of a virus-specific preinitiation complex. J Virol 88:12825–12838

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Baumann M, Feederle R, Kremmer E, Hammerschmidt W (1999) Cellular transcription factors recruit viral replication proteins to activate the Epstein-Barr virus origin of lytic DNA replication, oriLyt. EMBO J 18:6095–6105 (published erratum appears in EMBO J 2000 Jan 17; 19(2):315)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bejarano MT, Masucci MG (1998) Interleukin-10 abrogates the inhibition of Epstein-Barr virus-induced B-cell transformation by memory T-cell responses. Blood 92:4256–4262

    CAS  PubMed  Google Scholar 

  • Ben-Sasson SA, Klein G (1981) Activation of the Epstein-Barr virus genome by 5-aza-cytidine in latently infected human lymphoid lines. Int J Cancer 28:131–135

    Article  CAS  PubMed  Google Scholar 

  • Bergbauer M, Kalla M, Schmeinck A, Gobel C, Rothbauer U, Eck S, Benet-Pages A, Strom TM, Hammerschmidt W (2010) CpG-methylation regulates a class of Epstein-Barr virus promoters. PLoS Pathog 6:e1001114

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Bhaduri-McIntosh S, Miller G (2006) Cells lytically infected with Epstein-Barr virus are detected and separable by immunoglobulins from EBV-seropositive individuals. J Virol Methods 137:103–114

    Article  CAS  PubMed  Google Scholar 

  • Bhende PM, Seaman WT, Delecluse HJ, Kenney SC (2004) The EBV lytic switch protein, Z, preferentially binds to and activates the methylated viral genome. Nat Genet 36:1099–1104

    Article  CAS  PubMed  Google Scholar 

  • Bhende PM, Seaman WT, Delecluse HJ, Kenney SC (2005) BZLF1 activation of the methylated form of the BRLF1 immediate-early promoter is regulated by BZLF1 residue 186. J Virol 79:7338–7348

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bhende PM, Dickerson SJ, Sun X, Feng WH, Kenney SC (2007) X-box-binding protein 1 activates lytic Epstein-Barr virus gene expression in combination with protein kinase D. J Virol 81:7363–7370

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bloss TA, Sugden B (1994) Optimal lengths for DNAs encapsidated by Epstein-Barr virus. J Virol 68:8217–8222

    PubMed Central  CAS  PubMed  Google Scholar 

  • Borras AM, Strominger JL, Speck SH (1996) Characterization of the ZI domains in the Epstein-Barr virus BZLF1 gene promoter: role in phorbol ester induction. J Virol 70:3894–3901

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bryant H, Farrell PJ (2002) Signal transduction and transcription factor modification during reactivation of Epstein-Barr virus from latency. J Virol 76:10290–10298

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Buettner M, Lang A, Tudor CS, Meyer B, Cruchley A, Barros MH, Farrell PJ, Jack HM, Schuh W, Niedobitek G (2012) Lytic Epstein-Barr virus infection in epithelial cells but not in B-lymphocytes is dependent on Blimp1. J Gen Virol 93:1059–1064

    Article  CAS  PubMed  Google Scholar 

  • Cao SM, Liu Z, Jia WH, Huang QH, Liu Q, Guo X, Huang TB, Ye W, Hong MH (2011) Fluctuations of epstein-barr virus serological antibodies and risk for nasopharyngeal carcinoma: a prospective screening study with a 20-year follow-up. PLoS ONE 6:e19100

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chan CK, Mueller N, Evans A, Harris NL, Comstock GW, Jellum E, Magnus K, Orentreich N, Polk BF, Vogelman J (1991) Epstein-Barr virus antibody patterns preceding the diagnosis of nasopharyngeal carcinoma. Cancer Causes Control 2:125–131

    Article  CAS  PubMed  Google Scholar 

  • Chang LK, Liu ST (2000) Activation of the BRLF1 promoter and lytic cycle of Epstein-Barr virus by histone acetylation. Nucleic Acids Res 28:3918–3925

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chang LK, Chung JY, Hong YR, Ichimura T, Nakao M, Liu ST (2005) Activation of Sp1-mediated transcription by Rta of Epstein-Barr virus via an interaction with MCAF1. Nucleic Acids Res 33:6528–6539

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chang LK, Chuang JY, Nakao M, Liu ST (2010) MCAF1 and synergistic activation of the transcription of Epstein-Barr virus lytic genes by Rta and Zta. Nucleic Acids Res 38:4687–4700

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chatila T, Ho N, Liu P, Liu S, Mosialos G, Kieff E, Speck SH (1997) The Epstein-Barr virus-induced Ca2+/calmodulin-dependent kinase type IV/Gr promotes a Ca(2+)-dependent switch from latency to viral replication. J Virol 71:6560–6567

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chen JY, Hwang LY, Beasley RP, Chien CS, Yang CS (1985) Antibody response to Epstein-Barr-virus-specific DNase in 13 patients with nasopharyngeal carcinoma in Taiwan: a retrospective study. J Med Virol 16:99–105

    Article  CAS  PubMed  Google Scholar 

  • Chen CJ, Deng Z, Kim AY, Blobel GA, Lieberman PM (2001) Stimulation of CREB binding protein nucleosomal histone acetyltransferase activity by a class of transcriptional activators. Mol Cell Biol 21:476–487

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chen LW, Chang PJ, Delecluse HJ, Miller G (2005) Marked variation in response of consensus binding elements for the Rta protein of Epstein-Barr virus. J Virol 79:9635–9650

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chen LW, Raghavan V, Chang PJ, Shedd D, Heston L, Delecluse HJ, Miller G (2009) Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. Virology 386:448–461

    Article  CAS  PubMed  Google Scholar 

  • Chi T, Lieberman P, Ellwood K, Carey M (1995) A general mechanism for transcriptional synergy by eukaryotic activators. Nature 377:254–257

    Article  CAS  PubMed  Google Scholar 

  • Chien YC, Chen JY, Liu MY, Yang HI, Hsu MM, Chen CJ, Yang CS (2001) Serologic markers of Epstein-Barr virus infection and nasopharyngeal carcinoma in Taiwanese men. N Engl J Med 345:1877–1882

    Article  CAS  PubMed  Google Scholar 

  • Cho MS, Bornkamm GW, zur Hausen H (1984) Structure of defective DNA molecules in Epstein-Barr virus preparations from P3HR-1 cells. J Virol 51:199–207

    Google Scholar 

  • Countryman J, Miller G (1985) Activation of expression of latent Epstein-Barr herpesvirus after gene transfer with a small cloned subfragment of heterogeneous viral DNA. Proc Natl Acad Sci USA 82:4085–4089

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Countryman JK, Gradoville L, Miller G (2008) Histone hyperacetylation occurs on promoters of lytic cycle regulatory genes in Epstein-Barr virus-infected cell lines which are refractory to disruption of latency by histone deacetylase inhibitors. J Virol 82:4706–4719

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Crawford DH, Epstein MA, Bornkamm GW, Achong BG, Finerty S, Thompson JL (1979) Biological and biochemical observations on isolates of EB virus from the malignant epithelial cells of two nasopharyngeal carcinomas. Int J Cancer 24:294–302

    Article  CAS  PubMed  Google Scholar 

  • Daibata M, Speck SH, Mulder C, Sairenji T (1994) Regulation of the BZLF1 promoter of Epstein-Barr virus by second messengers in anti-immunoglobulin-treated B cells. Virology 198:446–454

    Article  CAS  PubMed  Google Scholar 

  • Daigle D, Megyola C, El-Guindy A, Gradoville L, Tuck D, Miller G, Bhaduri-McIntosh S (2010) Upregulation of STAT3 marks Burkitt lymphoma cells refractory to Epstein-Barr virus lytic cycle induction by HDAC inhibitors. J Virol 84:993–1004

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Daigle D, Gradoville L, Tuck D, Schulz V, Wang’ondu R, Ye J, Gorres K, Miller G (2011) Valproic acid antagonizes the capacity of other histone deacetylase inhibitors to activate the Epstein-barr virus lytic cycle. J Virol 85:5628–5643

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Daikoku T, Kudoh A, Fujita M, Sugaya Y, Isomura H, Shirata N, Tsurumi T (2005) Architecture of replication compartments formed during Epstein-Barr virus lytic replication. J Virol 79:3409–3418

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Darenkov IA, Marcarelli MA, Basadonna GP, Friedman AL, Lorber KM, Howe JG, Crouch J, Bia MJ, Kliger AS, Lorber MI (1997) Reduced incidence of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder using preemptive antiviral therapy. Transplantation 64:848–852

    Article  CAS  PubMed  Google Scholar 

  • Darr CD, Mauser A, Kenney S (2001) Epstein-Barr virus immediate-early protein BRLF1 induces the lytic form of viral replication through a mechanism involving phosphatidylinositol- 3 kinase activation. J Virol 75:6135–6142

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Davies AH, Grand RJ, Evans FJ, Rickinson AB (1991) Induction of Epstein-Barr virus lytic cycle by tumor-promoting and non-tumor-promoting phorbol esters requires active protein kinase C. J Virol 65:6838–6844

    PubMed Central  CAS  PubMed  Google Scholar 

  • Davies ML, Xu S, Lyons-Weiler J, Rosendorff A, Webber SA, Wasil LR, Metes D, Rowe DT (2010) Cellular factors associated with latency and spontaneous Epstein-Barr virus reactivation in B-lymphoblastoid cell lines. Virology 400:53–67

    Article  CAS  PubMed  Google Scholar 

  • Deng Z, Chen CJ, Zerby D, Delecluse HJ, Lieberman PM (2001) Identification of acidic and aromatic residues in the Zta activation domain essential for Epstein-Barr virus reactivation. J Virol 75:10334–10347

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dickerson SJ, Xing Y, Robinson AR, Seaman WT, Gruffat H, Kenney SC (2009) Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. PLoS Pathog 5:e1000356

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • El-Guindy AS, Miller G (2004) Phosphorylation of Epstein-Barr virus ZEBRA protein at its casein kinase 2 sites mediates its ability to repress activation of a viral lytic cycle late gene by Rta. J Virol 78:7634–7644

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • El-Guindy A, Heston L, Endo Y, Cho MS, Miller G (2002) Disruption of Epstein-Barr Virus Latency in the Absence of phosphorylation of ZEBRA by Protein Kinase C. J Virol 76:11199–11208

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • El-Guindy AS, Paek SY, Countryman J, Miller G (2006) Identification of constitutive phosphorylation sites on the Epstein-Barr virus ZEBRA protein. J Biol Chem 281:3085–3095

    Article  CAS  PubMed  Google Scholar 

  • El-Guindy A, Heston L, Delecluse HJ, Miller G (2007) Phosphoacceptor site S173 in the regulatory domain of Epstein-Barr virus ZEBRA protein is required for lytic DNA replication but not for activation of viral early genes. J Virol 81:3303–3316

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • El-Guindy A, Heston L, Miller G (2010) A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. PLoS Pathog 6

    Google Scholar 

  • El-Guindy A, Ghiassi-Nejad M, Golden S, Delecluse HJ, Miller G (2013) Essential role of rta in lytic DNA replication of Epstein-Barr virus. J Virol 87:208–223

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • El-Guindy A, Lopez-Giraldez F, Delecluse HJ, McKenzie J, Miller G (2014) A locus encompassing the Epstein-Barr virus bglf4 kinase regulates expression of genes encoding viral structural proteins. PLoS Pathog 10:e1004307

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Ellis AL, Wang Z, Yu X, Mertz JE (2010) Either ZEB1 or ZEB2/SIP1 can play a central role in regulating the Epstein-Barr virus latent-lytic switch in a cell-type-specific manner. J Virol 84:6139–6152

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ellis-Connell AL, Iempridee T, Xu I, Mertz JE (2010) Cellular microRNAs 200b and 429 regulate the Epstein-Barr virus switch between latency and lytic replication. J Virol 84:10329–10343

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fahmi H, Cochet C, Hmama Z, Opolon P, Joab I (2000) Transforming growth factor beta 1 stimulates expression of the Epstein-Barr virus BZLF1 immediate-early gene product ZEBRA by an indirect mechanism which requires the MAPK kinase pathway. J Virol 74:5810–5818

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Farmer DG, McDiarmid SV, Winston D, Yersiz H, Cortina G, Dry S, Maxfield AJ, Vandenbogaart B, Correa M, Kroeber A, Geevarghese S, Busuttil RW (2002) Effectiveness of aggressive prophylatic and preemptive therapies targeted against cytomegaloviral and Epstein-Barr viral disease after human intestinal transplantation. Transp Proc 34:948–949

    Article  CAS  Google Scholar 

  • Farrell PJ, Rowe DT, Rooney CM, Kouzarides T (1989) Epstein-Barr virus BZLF1 trans-activator specifically binds to a consensus AP-1 site and is related to c-fos. EMBO J 8:127–132

    PubMed Central  CAS  PubMed  Google Scholar 

  • Feederle R, Kost M, Baumann M, Janz A, Drouet E, Hammerschmidt W, Delecluse HJ (2000) The Epstein-Barr virus lytic program is controlled by the co-operative functions of two transactivators. EMBO J 19:3080–3089

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Feng WH, Kenney SC (2006) Valproic acid enhances the efficacy of chemotherapy in EBV-positive tumors by increasing lytic viral gene expression. Cancer Res 66:8762–8769

    Article  CAS  PubMed  Google Scholar 

  • Feng WH, Israel B, Raab-Traub N, Busson P, Kenney SC (2002) Chemotherapy induces lytic EBV replication and confers ganciclovir susceptibility to EBV-positive epithelial cell tumors. Cancer Res 62:1920–1926

    CAS  PubMed  Google Scholar 

  • Feng WH, Hong G, Delecluse HJ, Kenney SC (2004) Lytic induction therapy for Epstein-Barr virus-positive B-cell lymphomas. J Virol 78:1893–1902

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Feng WH, Kraus RJ, Dickerson SJ, Lim HJ, Jones RJ, Yu X, Mertz JE, Kenney SC (2007) ZEB1 and c-Jun levels contribute to the establishment of highly lytic Epstein-Barr virus infection in gastric AGS cells. J Virol 81:10113–10122

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fixman ED, Hayward GS, Hayward SD (1992) trans-acting requirements for replication of Epstein-Barr virus ori-Lyt. J Virol 66:5030–5039

    PubMed Central  CAS  PubMed  Google Scholar 

  • Fixman ED, Hayward GS, Hayward SD (1995) Replication of Epstein-Barr virus oriLyt: lack of a dedicated virally encoded origin-binding protein and dependence on Zta in cotransfection assays. J Virol 69:2998–3006

    PubMed Central  CAS  PubMed  Google Scholar 

  • Flamand L, Menezes J (1996) Cyclic AMP-responsive element-dependent activation of Epstein-Barr virus zebra promoter by human herpesvirus 6. J Virol 70:1784–1791

    PubMed Central  CAS  PubMed  Google Scholar 

  • Flemington E, Speck SH (1990a) Autoregulation of Epstein-Barr virus putative lytic switch gene BZLF1. J Virol 64:1227–1232

    PubMed Central  CAS  PubMed  Google Scholar 

  • Flemington E, Speck SH (1990b) Epstein-Barr virus BZLF1 trans activator induces the promoter of a cellular cognate gene, c-fos. J Virol 64:4549–4552

    PubMed Central  CAS  PubMed  Google Scholar 

  • Flemington E, Speck SH (1990c) Identification of phorbol ester response elements in the promoter of Epstein-Barr virus putative lytic switch gene BZLF1. J Virol 64:1217–1226

    PubMed Central  CAS  PubMed  Google Scholar 

  • Flemington EK, Borras AM, Lytle JP, Speck SH (1992) Characterization of the Epstein-Barr virus BZLF1 protein transactivation domain. J Virol 66:922–929

    PubMed Central  CAS  PubMed  Google Scholar 

  • Francis AL, Gradoville L, Miller G (1997) Alteration of a single serine in the basic domain of the Epstein-Barr virus ZEBRA protein separates its functions of transcriptional activation and disruption of latency. J Virol 71:3054–3061

    PubMed Central  CAS  PubMed  Google Scholar 

  • Francis A, Ragoczy T, Gradoville L, El-Guindy A, Miller G (1999) Amino Acid substitutions reveal distinct functions of serine 186 of the ZEBRA protein in activation of lytic cycle genes and synergy with the EBV Rta transactivator. J Virol 73:4543–4551

    PubMed Central  CAS  PubMed  Google Scholar 

  • Fruehling S, Longnecker R (1997) The immunoreceptor tyrosine-based activation motif of Epstein-Barr virus LMP2A is essential for blocking BCR-mediated signal transduction. Virology 235:241–251

    Article  CAS  PubMed  Google Scholar 

  • Fu DX, Tanhehco Y, Chen J, Foss CA, Fox JJ, Chong JM, Hobbs RF, Fukayama M, Sgouros G, Kowalski J, Pomper MG, Ambinder RF (2008) Bortezomib-induced enzyme-targeted radiation therapy in herpesvirus-associated tumors. Nat Med 14:1118–1122

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gao Z, Krithivas A, Finan JE, Semmes OJ, Zhou S, Wang Y, Hayward SD (1998) The Epstein-Barr virus lytic transactivator Zta interacts with the helicase-primase replication proteins. J Virol 72:8559–8567

    PubMed Central  CAS  PubMed  Google Scholar 

  • Glover JN, Harrison SC (1995) Crystal structure of the heterodimeric bZIP transcription factor c-Fos- c-Jun bound to DNA. Nature 373:257–261

    Article  CAS  PubMed  Google Scholar 

  • Goswami R, Gershburg S, Satorius A, Gershburg E (2012) Protein kinase inhibitors that inhibit induction of lytic program and replication of Epstein-Barr virus. Antiviral Res 96:296–304

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Green M (2001) Management of Epstein-Barr virus-induced post-transplant lymphoproliferative disease in recipients of solid organ transplantation. Am J Transp 1:103–108

    CAS  Google Scholar 

  • Grogan EJ, Jenson J, Countryman J, Heston L, Gradoville L, Miller G (1987) Transfection of a rearranged viral DNA fragment WZhet, stably converts latent Epstein-Barr virus infection to productive infection in lymphoid cells. Proc Natl Acad Sci USA 84:1332–1336

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gruffat H, Manet E, Rigolet A, Sergeant A (1990) The enhancer factor R of Epstein-Barr virus (EBV) is a sequence- specific DNA binding protein. Nucleic Acids Res 18:6835–6843

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gruffat H, Manet E, Sergeant A (2002) MEF2-mediated recruitment of class II HDAC at the EBV immediate early gene BZLF1 links latency and chromatin remodeling. EMBO Rep 3:141–146

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gruffat H, Kadjouf F, Mariame B, Manet E (2012) The Epstein-Barr virus BcRF1 gene product is a TBP-like protein with an essential role in late gene expression. J Virol 86:6023–6032

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hadinoto V, Shapiro M, Sun CC, Thorley-Lawson DA (2009) The dynamics of EBV shedding implicate a central role for epithelial cells in amplifying viral output. PLoS Pathog 5:e1000496

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Hagemeier SR, Dickerson SJ, Meng Q, Yu X, Mertz JE, Kenney SC (2010) Sumoylation of the Epstein-Barr virus BZLF1 protein inhibits its transcriptional activity and is regulated by the virus-encoded protein kinase. J Virol 84:4383–4394

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hagemeier SR, Barlow EA, Kleman AA, Kenney SC (2011) The Epstein-Barr virus BRRF1 protein, Na, induces lytic infection in a TRAF2- and p53-dependent manner. J Virol 85:4318–4329

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hagemeier SR, Barlow EA, Meng Q, Kenney SC (2012) The cellular ataxia telangiectasia-mutated kinase promotes Epstein-Barr virus lytic reactivation in response to multiple different types of lytic reactivation-inducing stimuli. J Virol 86:13360–13370

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hammerschmidt W, Sugden B (1988) Identification and characterization of oriLyt, a lytic origin of DNA replication of Epstein-Barr virus. Cell 55:427–433

    Article  CAS  PubMed  Google Scholar 

  • Hammerschmidt W, Sugden B (2013) Replication of Epstein-Barr viral DNA. Cold Spring Harb Perspect Biol 5:a013029

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Heilmann AM, Calderwood MA, Johannsen E (2010) Epstein-Barr virus LF2 protein regulates viral replication by altering Rta subcellular localization. J Virol 84:9920–9931

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Heilmann AM, Calderwood MA, Portal D, Lu Y, Johannsen E (2012) Genome-wide analysis of Epstein-Barr virus Rta DNA binding. J Virol 86:5151–5164

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Henle G, Henle W (1966) Immunofluorescence in cells derived from Burkitt’s lymphoma. J Bacteriol 91:1248–1256

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hill ER, Koganti S, Zhi J, Megyola C, Freeman AF, Palendira U, Tangye SG, Farrell PJ, Bhaduri-McIntosh S (2013) Signal transducer and activator of transcription 3 limits Epstein-Barr virus lytic activation in B lymphocytes. J Virol 87:11438–11446

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hong GK, Delecluse HJ, Gruffat H, Morrison TE, Feng WH, Sergeant A, Kenney SC (2004) The BRRF1 early gene of Epstein-Barr virus encodes a transcription factor that enhances induction of lytic infection by BRLF1. J Virol 78:4983–4992

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hong GK, Gulley ML, Feng WH, Delecluse HJ, Holley-Guthrie E, Kenney SC (2005) Epstein-Barr virus lytic infection contributes to lymphoproliferative disease in a SCID mouse model. J Virol 79:13993–14003

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hsu M, Wu SY, Chang SS, Su IJ, Tsai CH, Lai SJ, Shiau AL, Takada K, Chang Y (2008) Epstein-Barr virus lytic transactivator Zta enhances chemotactic activity through induction of interleukin-8 in nasopharyngeal carcinoma cells. J Virol 82:3679–3688

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hsu WL, Chen JY, Chien YC, Liu MY, You SL, Hsu MM, Yang CS, Chen CJ (2009) Independent effect of EBV and cigarette smoking on nasopharyngeal carcinoma: a 20-year follow-up study on 9,622 males without family history in Taiwan. Cancer Epidemiol Biomark Prev 18:1218–1226

    Article  CAS  Google Scholar 

  • Huang J, Liao G, Chen H, Wu FY, Hutt-Fletcher L, Hayward GS, Hayward SD (2006) Contribution of C/EBP proteins to Epstein-Barr virus lytic gene expression and replication in epithelial cells. J Virol 80:1098–1109

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Iempridee T, Das S, Xu I, Mertz JE (2011) Transforming growth factor beta-induced reactivation of Epstein-Barr virus involves multiple Smad-binding elements cooperatively activating expression of the latent-lytic switch BZLF1 gene. J Virol 85:7836–7848

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Iwakiri D, Takada K (2004) Phosphatidylinositol 3-kinase is a determinant of responsiveness to B cell antigen receptor-mediated Epstein-Barr virus activation. J Immunol 172:1561–1566

    Article  CAS  PubMed  Google Scholar 

  • Jacob RJ, Roizman B (1977) Anatomy of herpes simplex virus DNA VIII. Properties of the replicating DNA. J Virol 23:394–411

    PubMed Central  CAS  PubMed  Google Scholar 

  • Jenkins PJ, Binne UK, Farrell PJ (2000) Histone acetylation and reactivation of Epstein-Barr virus from latency. J Virol 74:710–720

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jiang JH, Wang N, Li A, Liao WT, Pan ZG, Mai SJ, Li DJ, Zeng MS, Wen JM, Zeng YX (2006) Hypoxia can contribute to the induction of the Epstein-Barr virus (EBV) lytic cycle. J Clin Virol 37:98–103

    Article  CAS  PubMed  Google Scholar 

  • Kalla M, Hammerschmidt W (2012) Human B cells on their route to latent infection–early but transient expression of lytic genes of Epstein-Barr virus. Eur J Cell Biol 91:65–69

    Article  CAS  PubMed  Google Scholar 

  • Kalla M, Schmeinck A, Bergbauer M, Pich D, Hammerschmidt W (2010) AP-1 homolog BZLF1 of Epstein-Barr virus has two essential functions dependent on the epigenetic state of the viral genome. Proc Natl Acad Sci USA 107:850–855

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kalla M, Gobel C, Hammerschmidt W (2012) The lytic phase of Epstein-Barr virus requires a viral genome with 5-methylcytosine residues in CpG sites. J Virol 86:447–458

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Karimi L, Crawford DH, Speck S, Nicholson LJ (1995) Identification of an epithelial cell differentiation responsive region within the BZLF1 promoter of the Epstein-Barr virus. J Gen Virol 76:759–765

    Article  CAS  PubMed  Google Scholar 

  • Katsumura KR, Maruo S, Takada K (2012) EBV lytic infection enhances transformation of B-lymphocytes infected with EBV in the presence of T-lymphocytes. J Med Virol 84:504–510

    Article  CAS  PubMed  Google Scholar 

  • Kenney SC, Mertz JE (2014) Regulation of the latent-lytic switch in Epstein-Barr virus. Semin Cancer Biol

    Google Scholar 

  • Kintner C, Sugden B (1981) Conservation and progressive methylation of Epstein-Barr viral DNA sequences in transformed cells. J Virol 38:305–316

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kouzarides T, Packham G, Cook A, Farrell PJ (1991) The BZLF1 protein of EBV has a coiled coil dimerisation domain without a heptad leucine repeat but with homology to the C/EBP leucine zipper. Oncogene 6:195–204

    CAS  PubMed  Google Scholar 

  • Kraus RJ, Perrigoue JG, Mertz JE (2003) ZEB negatively regulates the lytic-switch BZLF1 gene promoter of Epstein-Barr virus. J Virol 77:199–207

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kutok JL, Wang F (2006) Spectrum of Epstein-Barr virus-associated diseases. Annu Rev Pathol 1:375–404

    Article  CAS  PubMed  Google Scholar 

  • Lai IY, Farrell PJ, Kellam P (2011) X-box binding protein 1 induces the expression of the lytic cycle transactivator of Kaposi’s sarcoma-associated herpesvirus but not Epstein-Barr virus in co-infected primary effusion lymphoma. J Gen Virol 92:421–431

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lee TC, Savoldo B, Rooney CM, Heslop HE, Gee AP, Caldwell Y, Barshes NR, Scott JD, Bristow LJ, O’Mahony CA, Goss JA (2005) Quantitative EBV viral loads and immunosuppression alterations can decrease PTLD incidence in pediatric liver transplant recipients. Am J Transp (Official Journal of The American Society of Transplantation and the American Society of Transplant Surgeons) 5:2222–2228

    Article  Google Scholar 

  • Lehman AM, Ellwood KB, Middleton BE, Carey M (1998) Compensatory energetic relationships between upstream activators and the RNA polymerase II general transcription machinery. J Biol Chem 273:932–939

    Article  CAS  PubMed  Google Scholar 

  • Lemon SM, Hutt LM, Shaw JE, Li JL, Pagano JS (1978) Replication of Epstein-Barr virus DNA in epithelial cells in vivo. IARC Sci Publ 739–744

    Google Scholar 

  • Li M, Linseman DA, Allen MP, Meintzer MK, Wang X, Laessig T, Wierman ME, Heidenreich KA (2001) Myocyte enhancer factor 2A and 2D undergo phosphorylation and caspase-mediated degradation during apoptosis of rat cerebellar granule neurons. J Neurosci 21:6544–6552

    CAS  PubMed  Google Scholar 

  • Liang CL, Chen JL, Hsu YP, Ou JT, Chang YS (2002) Epstein-Barr virus BZLF1 gene is activated by transforming growth factor-beta through cooperativity of Smads and c-Jun/c-Fos proteins. J Biol Chem 277:23345–23357

    Article  CAS  PubMed  Google Scholar 

  • Liang X, Collins CM, Mendel JB, Iwakoshi NN, Speck SH (2009) Gammaherpesvirus-driven plasma cell differentiation regulates virus reactivation from latently infected B lymphocytes. PLoS Pathog 5:e1000677

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Liao G, Huang J, Fixman ED, Hayward SD (2005) The Epstein-Barr virus replication protein BBLF2/3 provides an origin-tethering function through interaction with the zinc finger DNA binding protein ZBRK1 and the KAP-1 corepressor. J Virol 79:245–256

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lieberman PM, Berk AJ (1991) The Zta trans-activator protein stabilizes TFIID association with promoter DNA by direct protein-protein interaction. Genes Dev 5:2441–2454

    Article  CAS  PubMed  Google Scholar 

  • Lieberman PM, Berk AJ (1994) A mechanism for TAFs in transcriptional activation: activation domain enhancement of TFIID-TFIIA–promoter DNA complex formation. Genes Dev 8:995–1006

    Article  CAS  PubMed  Google Scholar 

  • Lieberman PM, Hardwick JM, Sample J, Hayward GS, Hayward SD (1990) The zta transactivator involved in induction of lytic cycle gene expression in Epstein-Barr virus-infected lymphocytes binds to both AP-1 and ZRE sites in target promoter and enhancer regions. J Virol 64:1143–1155

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lin Z, Wang X, Fewell C, Cameron J, Yin Q, Flemington EK (2010) Differential expression of the miR-200 family microRNAs in epithelial and B cells and regulation of Epstein-Barr virus reactivation by the miR-200 family member miR-429. J Virol 84:7892–7897

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Liu C, Sista ND, Pagano JS (1996) Activation of the Epstein-Barr virus DNA polymerase promoter by the BRLF1 immediate-early protein is mediated through USF and E2F. J Virol 70:2545–2555

    PubMed Central  CAS  PubMed  Google Scholar 

  • Liu S, Borras AM, Liu P, Suske G, Speck SH (1997a) Binding of the ubiquitous cellular transcription factors Sp1 and Sp3 to the ZI domains in the Epstein-Barr virus lytic switch BZLF1 gene promoter. Virology 228:11–18

    Article  CAS  PubMed  Google Scholar 

  • Liu S, Liu P, Borras A, Chatila T, Speck SH (1997b) Cyclosporin A-sensitive induction of the Epstein-Barr virus lytic switch is mediated via a novel pathway involving a MEF2 family member. EMBO J 16:143–153

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Liu P, Liu S, Speck SH (1998) Identification of a negative cis element within the ZII domain of the Epstein-Barr virus lytic switch BZLF1 gene promoter. J Virol 72:8230–8239

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lu CC, Jeng YY, Tsai CH, Liu MY, Yeh SW, Hsu TY, Chen MR (2006) Genome-wide transcription program and expression of the Rta responsive gene of Epstein-Barr virus. Virology 345:358–372

    Article  CAS  PubMed  Google Scholar 

  • Lucas KG, Burton RL, Zimmerman SE, Wang J, Cornetta KG, Robertson KA, Lee CH, Emanuel DJ (1998) Semiquantitative Epstein-Barr virus (EBV) polymerase chain reaction for the determination of patients at risk for EBV-induced lymphoproliferative disease after stem cell transplantation. Blood 91:3654–3661

    CAS  PubMed  Google Scholar 

  • Luka J, Kallin B, Klein G (1979) Induction of the Epstein-Barr virus (EBV) cycle in latently infected cells by n-butyrate. Virology 94:228–231

    Article  CAS  PubMed  Google Scholar 

  • Ma SD, Hegde S, Young KH, Sullivan R, Rajesh D, Zhou Y, Jankowska-Gan E, Burlingham WJ, Sun X, Gulley ML, Tang W, Gumperz JE, Kenney SC (2011) A new model of Epstein-Barr virus infection reveals an important role for early lytic viral protein expression in the development of lymphomas. J Virol 85:165–177

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Manet E, Rigolet A, Gruffat H, Giot JF, Sergeant A (1991) Domains of the Epstein-Barr virus (EBV) transcription factor R required for dimerization, DNA binding and activation. Nucleic Acids Res 19:2661–2667

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Manet E, Allera C, Gruffat H, Mikaelian I, Rigolet A, Sergeant A (1993) The acidic activation domain of the Epstein-Barr virus transcription factor R interacts in vitro with both TBP and TFIIB and is cell- specifically potentiated by a proline-rich region. Gene Expr 3:49–59

    CAS  PubMed  Google Scholar 

  • Mansouri S, Wang S, Frappier L (2013) A role for the nucleosome assembly proteins TAF-Ibeta and NAP1 in the activation of BZLF1 expression and Epstein-Barr virus reactivation. PLoS ONE 8:e63802

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Matsuzaki K (2011) Smad phosphoisoform signaling specificity: the right place at the right time. Carcinogenesis 32:1578–1588

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • McDiarmid SV, Jordan S, Kim GS, Toyoda M, Goss JA, Vargas JH, Martin MG, Bahar R, Maxfield AL, Ament ME, Busuttil RW (1998) Prevention and preemptive therapy of postransplant lymphoproliferative disease in pediatric liver recipients. Transplantation 66:1604–1611

    Article  CAS  PubMed  Google Scholar 

  • McDonald C, Karstegl CE, Kellam P, Farrell PJ (2010) Regulation of the Epstein-Barr virus Zp promoter in B lymphocytes during reactivation from latency. J Gen Virol 91:622–629

    Article  CAS  PubMed  Google Scholar 

  • Meng Q, Hagemeier SR, Fingeroth JD, Gershburg E, Pagano JS, Kenney SC (2010) The Epstein-Barr virus (EBV)-encoded protein kinase, EBV-PK, but not the thymidine kinase (EBV-TK), is required for ganciclovir and acyclovir inhibition of lytic viral production. J Virol 84:4534–4542

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Miller MH, Stitt D, Miller G (1970) Epstein-Barr viral antigen in single cell clones of two human leukocytic lines. J Virol 6:699–701

    PubMed Central  CAS  PubMed  Google Scholar 

  • Miller G, Robinson J, Heston L, Lipman M (1974) Differences between laboratory strains of Epstein-Barr virus based on immortalization, abortive infection, and interference. Proc Natl Acad Sci USA 71:4006–4010

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Miller G, El-Guindy A, Countryman J, Ye J, Gradoville L (2007) Lytic cycle switches of oncogenic human gammaherpesviruses. Adv Cancer Res 97:81–109

    Article  CAS  PubMed  Google Scholar 

  • Mueller N, Evans A, Harris NL, Comstock GW, Jellum E, Magnus K, Orentreich N, Polk BF, Vogelman J (1989) Hodgkin’s disease and Epstein-Barr virus. Altered antibody pattern before diagnosis. N Engl J Med 320:689–695

    Article  CAS  PubMed  Google Scholar 

  • Mueller N, Mohar A, Evans A, Harris NL, Comstock GW, Jellum E, Magnus K, Orentreich N, Polk BF, Vogelman J (1991) Epstein-Barr virus antibody patterns preceding the diagnosis of non-Hodgkin’s lymphoma. Int J Cancer 49:387–393

    Article  CAS  PubMed  Google Scholar 

  • Murata T, Noda C, Saito S, Kawashima D, Sugimoto A, Isomura H, Kanda T, Yokoyama KK, Tsurumi T (2011) Involvement of Jun dimerization protein 2 (JDP2) in the maintenance of Epstein-Barr virus latency. J Biol Chem 286:22007–22016

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Murata T, Kondo Y, Sugimoto A, Kawashima D, Saito S, Isomura H, Kanda T, Tsurumi T (2012) Epigenetic histone modification of Epstein-Barr virus BZLF1 promoter during latency and reactivation in Raji cells. J Virol 86:4752–4761

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Murata T, Narita Y, Sugimoto A, Kawashima D, Kanda T, Tsurumi T (2013) Contribution of myocyte enhancer factor 2 family transcription factors to BZLF1 expression in Epstein-Barr virus reactivation from latency. J Virol 87:10148–10162

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Packard TA, Cambier JC (2013) B lymphocyte antigen receptor signaling: initiation, amplification, and regulation. F1000Prime Rep 5:40

    Google Scholar 

  • Park SM, Gaur AB, Lengyel E, Peter ME (2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22:894–907

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Perrine SP, Hermine O, Small T, Suarez F, O’Reilly R, Boulad F, Fingeroth J, Askin M, Levy A, Mentzer SJ, Di Nicola M, Gianni AM, Klein C, Horwitz S, Faller DV (2007) A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus-associated lymphoid malignancies. Blood 109:2571–2578

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Petosa C, Morand P, Baudin F, Moulin M, Artero JB, Muller CW (2006) Structural basis of lytic cycle activation by the Epstein-Barr virus ZEBRA protein. Mol Cell 21:565–572

    Article  CAS  PubMed  Google Scholar 

  • Pfuller R, Hammerschmidt W (1996) Plasmid-like replicative intermediates of the Epstein-Barr virus lytic origin of DNA replication. J Virol 70:3423–3431

    PubMed Central  CAS  PubMed  Google Scholar 

  • Quinlivan EB, Holley-Guthrie EA, Norris M, Gutsch D, Bachenheimer SL, Kenney SC (1993) Direct BRLF1 binding is required for cooperative BZLF1/BRLF1 activation of the Epstein-Barr virus early promoter, BMRF1. Nucleic Acids Res 21:1999–2007 (corrected and republished with original paging, article originally printed in Nucleic Acids Res 1993 Apr 25; 21(8):1999–2007)

    Google Scholar 

  • Quinn ZA, Yang CC, Wrana JL, McDermott JC (2001) Smad proteins function as co-modulators for MEF2 transcriptional regulatory proteins. Nucleic Acids Res 29:732–742

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Raab-Traub N, Dambaugh T, Kieff E (1980) DNA of Epstein-Barr virus VIII: B95-8, the previous prototype, is an unusual deletion derivative. Cell 22:257–267

    Article  CAS  PubMed  Google Scholar 

  • Ragoczy T, Miller G (1999) Role of the Epstein-Barr virus RTA protein in activation of distinct classes of viral lytic cycle genes. J Virol 73:9858–9866

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ragoczy T, Heston L, Miller G (1998) The Epstein-Barr virus Rta protein activates lytic cycle genes and can disrupt latency in B lymphocytes. J Virol 72:7978–7984

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ramasubramanyan S, Osborn K, Flower K, Sinclair AJ (2012) Dynamic chromatin environment of key lytic cycle regulatory regions of the Epstein-Barr virus genome. J Virol 86:1809–1819

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rasche L, Kapp M, Einsele H, Mielke S (2013) EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoetic SCT. Bone Marrow Transp

    Google Scholar 

  • Raver RM, Panfil AR, Hagemeier SR, Kenney SC (2013) The B-cell-specific transcription factor and master regulator Pax5 promotes Epstein-Barr virus latency by negatively regulating the viral immediate early protein BZLF1. J Virol 87:8053–8063

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rennekamp AJ, Lieberman PM (2011) Initiation of Epstein-Barr virus lytic replication requires transcription and the formation of a stable RNA-DNA hybrid molecule at OriLyt. J Virol 85:2837–2850

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Reusch JA, Nawandar DM, Wright KL, Kenney SC, Mertz JE (2014) Cellular differentiation regulator BLIMP1 induces Epstein-Barr virus lytic reactivation in epithelial and B cells by activating transcription from both the R and Z promoters. J Virol

    Google Scholar 

  • Robinson AR, Kwek SS, Hagemeier SR, Wille CK, Kenney SC (2011) Cellular transcription factor Oct-1 interacts with the Epstein-Barr virus BRLF1 protein to promote disruption of viral latency. J Virol 85:8940–8953

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Robinson AR, Kwek SS, Kenney SC (2012) The B-cell specific transcription factor, Oct-2, promotes Epstein-Barr virus latency by inhibiting the viral immediate-early protein, BZLF1. PLoS Pathog 8:e1002516

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rooney C, Taylor N, Countryman J, Jenson H, Kolman J, Miller G (1988) Genome rearrangements activate the Epstein-Barr virus gene whose product disrupts latency. Proc Natl Acad Sci USA 85:9801–9805

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rooney CM, Loftin SK, Holladay MS, Brenner MK, Krance RA, Heslop HE (1995) Early identification of Epstein-Barr virus-associated post-transplantation lymphoproliferative disease. Br J Haematol 89:98–103

    Article  CAS  PubMed  Google Scholar 

  • Satoh T, Hoshikawa Y, Satoh Y, Kurata T, Sairenji T (1999) The interaction of mitogen-activated protein kinases to Epstein-Barr virus activation in Akata cells. Virus Genes 18:57–64

    Article  CAS  PubMed  Google Scholar 

  • Schepers A, Pich D, Mankertz J, Hammerschmidt W (1993) cis-acting elements in the lytic origin of DNA replication of Epstein-Barr virus. J Virol 67:4237–4245

    PubMed Central  CAS  PubMed  Google Scholar 

  • Serio TR, Kolman JL, Miller G (1997) Late gene expression from the Epstein-Barr virus BcLF1 and BFRF3 promoters does not require DNA replication in cis. J Virol 71:8726–8734

    PubMed Central  CAS  PubMed  Google Scholar 

  • Serio TR, Cahill N, Prout ME, Miller G (1998) A functionally distinct TATA box required for late progression through the Epstein-Barr virus life cycle. J Virol 72:8338–8343

    PubMed Central  CAS  PubMed  Google Scholar 

  • Seto E, Moosmann A, Gromminger S, Walz N, Grundhoff A, Hammerschmidt W (2010) Micro RNAs of Epstein-Barr virus promote cell cycle progression and prevent apoptosis of primary human B cells. PLoS Pathog 6:e1001063

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Shinozaki A, Sakatani T, Ushiku T, Hino R, Isogai M, Ishikawa S, Uozaki H, Takada K, Fukayama M (2010) Downregulation of microRNA-200 in EBV-associated gastric carcinoma. Cancer Res 70:4719–4727

    Article  CAS  PubMed  Google Scholar 

  • Shirley CM, Chen J, Shamay M, Li H, Zahnow CA, Hayward SD, Ambinder RF (2011) Bortezomib induction of C/EBPbeta mediates Epstein-Barr virus lytic activation in Burkitt lymphoma. Blood 117:6297–6303

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sixbey JW, Vesterinen EH, Nedrud JG, Raab-Traub N, Walton LA, Pagano JS (1983) Replication of Epstein-Barr virus in human epithelial cells infected in vitro. Nature 306:480–483

    Article  CAS  PubMed  Google Scholar 

  • Sixbey JW, Nedrud JG, Raab-Traub N, Hanes RA, Pagano JS (1984) Epstein-Barr virus replication in oropharyngeal epithelial cells. N Engl J Med 310:1225–1230

    Article  CAS  PubMed  Google Scholar 

  • Summers WC, Klein G (1976) Inhibition of Epstein-Barr virus DNA synthesis and late gene expression by phosphonoacetic acid. J Virol 18:151–155

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sun CC, Thorley-Lawson DA (2007) Plasma cell-specific transcription factor XBP-1s binds to and transactivates the Epstein-Barr virus BZLF1 promoter. J Virol 81:13566–13577

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Swenson JJ, Holley-Guthrie E, Kenney SC (2001) Epstein-Barr virus immediate-early protein BRLF1 interacts with CBP, promoting enhanced BRLF1 transactivation. J Virol 75:6228–6234

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Takada K (1984) Cross-linking of cell surface immunoglobulins induces Epstein-Barr virus in Burkitt lymphoma lines. Int J Cancer 33:27–32

    Article  CAS  PubMed  Google Scholar 

  • Takada K, Ono Y (1989) Synchronous and sequential activation of latently infected Epstein-Barr virus genomes. J Virol 63:445–449

    PubMed Central  CAS  PubMed  Google Scholar 

  • Taylor GM, Raghuwanshi SK, Rowe DT, Wadowsky RM, Rosendorff A (2011) Endoplasmic reticulum stress causes EBV lytic replication. Blood 118:5528–5539

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tikhmyanova N, Schultz DC, Lee T, Salvino JM, Lieberman PM (2014) Identification of a new class of small molecules that efficiently reactivate latent Epstein-Barr virus. ACS Chem Biol 9:785–795

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tovey MG, Lenoir G, Begon-Lours J (1978) Activation of latent Epstein-Barr virus by antibody to human IgM. Nature 276:270–272

    Article  CAS  PubMed  Google Scholar 

  • Tsai DE, Douglas L, Andreadis C, Vogl DT, Arnoldi S, Kotloff R, Svoboda J, Bloom RD, Olthoff KM, Brozena SC, Schuster SJ, Stadtmauer EA, Robertson ES, Wasik MA, Ahya VN (2008) EBV PCR in the diagnosis and monitoring of posttransplant lymphoproliferative disorder: results of a two-arm prospective trial. Am J Transp 8:1016–1024 (Official Journal of The American Society of Transplantation and The American Society of Transplant Surgeons)

    Article  CAS  Google Scholar 

  • Tsai PF, Lin SJ, Weng PL, Tsai SC, Lin JH, Chou YC, Tsai CH (2011) Interplay between PKCdelta and Sp1 on histone deacetylase inhibitor-mediated Epstein-Barr virus reactivation. J Virol 85:2373–2385

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tsai MH, Raykova A, Klinke O, Bernhardt K, Gartner K, Leung CS, Geletneky K, Sertel S, Munz C, Feederle R, Delecluse HJ (2013) Spontaneous lytic replication and epitheliotropism define an Epstein-Barr virus strain found in carcinomas. Cell Rep 5:458–470

    Article  CAS  PubMed  Google Scholar 

  • van Esser JW, van der Holt B, Meijer E, Niesters HG, Trenschel R, Thijsen SF, van Loon AM, Frassoni F, Bacigalupo A, Schaefer UW, Osterhaus AD, Gratama JW, Lowenberg B, Verdonck LF, Cornelissen JJ (2001) Epstein-Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell–depleted SCT. Blood 98:972–978

    Article  PubMed  Google Scholar 

  • Wang YC, Huang JM, Montalvo EA (1997) Characterization of proteins binding to the ZII element in the Epstein-Barr virus BZLF1 promoter: transactivation by ATF1. Virology 227:323–330

    Article  CAS  PubMed  Google Scholar 

  • Wang P, Day L, Dheekollu J, Lieberman PM (2005) A redox-sensitive cysteine in Zta is required for Epstein-Barr virus lytic cycle DNA replication. J Virol 79:13298–13309

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wen W, Iwakiri D, Yamamoto K, Maruo S, Kanda T, Takada K (2007) Epstein-Barr virus BZLF1 gene, a switch from latency to lytic infection, is expressed as an immediate-early gene after primary infection of B lymphocytes. J Virol 81:1037–1042

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wildeman MA, Novalic Z, Verkuijlen SA, Juwana H, Huitema AD, Tan IB, Middeldorp JM, de Boer JP, Greijer AE (2012) Cytolytic virus activation therapy for Epstein-Barr virus-driven tumors. Clin Cancer Res 18:5061–5070

    Article  CAS  PubMed  Google Scholar 

  • Wu FY, Wang SE, Chen H, Wang L, Hayward SD, Hayward GS (2004) CCAAT/enhancer binding protein alpha binds to the Epstein-Barr virus (EBV) ZTA protein through oligomeric interactions and contributes to cooperative transcriptional activation of the ZTA promoter through direct binding to the ZII and ZIIIB motifs during induction of the EBV lytic cycle. J Virol 78:4847–4865

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wyrwicz LS, Rychlewski L (2007) Identification of Herpes TATT-binding protein. Antiviral Res 75:167–172

    Article  CAS  PubMed  Google Scholar 

  • Ye J, Gradoville L, Daigle D, Miller G (2007) De novo protein synthesis is required for lytic cycle reactivation of Epstein-Barr virus, but not Kaposi’s sarcoma-associated herpesvirus, in response to histone deacetylase inhibitors and protein kinase C agonists. J Virol 81:9279–9291

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yin Q, Jupiter K, Flemington EK (2004) The Epstein-Barr virus transactivator Zta binds to its own promoter and is required for full promoter activity during anti-Ig and TGF-beta1 mediated reactivation. Virology 327:134–143

    Article  CAS  PubMed  Google Scholar 

  • Yu X, Wang Z, Mertz JE (2007) ZEB1 regulates the latent-lytic switch in infection by Epstein-Barr virus. PLoS Pathog 3:e194

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Yu X, McCarthy PJ, Lim HJ, Iempridee T, Kraus RJ, Gorlen DA, Mertz JE (2011) The ZIIR element of the Epstein-Barr virus BZLF1 promoter plays a central role in establishment and maintenance of viral latency. J Virol 85:5081–5090

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yu X, McCarthy PJ, Wang Z, Gorlen DA, Mertz JE (2012) Shutoff of BZLF1 gene expression is necessary for immortalization of primary B cells by Epstein-Barr virus. J Virol 86:8086–8096

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yu KP, Heston L, Park R, Ding Z, Wang’ondu R, Delecluse HJ, Miller G (2013) Latency of Epstein-Barr virus is disrupted by gain-of-function mutant cellular AP-1 proteins that preferentially bind methylated DNA. Proc Natl Acad Sci USA 110:8176–8181

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yuan J, Cahir-McFarland E, Zhao B, Kieff E (2006) Virus and cell RNAs expressed during Epstein-Barr virus replication. J Virol 80:2548–2565

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zacny VL, Wilson J, Pagano JS (1998) The Epstein-Barr virus immediate-early gene product, BRLF1, interacts with the retinoblastoma protein during the viral lytic cycle. J Virol 72:8043–8051

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zalani S, Holley-Guthrie E, Kenney S (1996) Epstein-Barr viral latency is disrupted by the immediate-early BRLF1 protein through a cell-specific mechanism. Proc Natl Acad Sci USA 93:9194–9199

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zeidler R, Eissner G, Meissner P, Uebel S, Tampe R, Lazis S, Hammerschmidt W (1997) Downregulation of TAP1 in B lymphocytes by cellular and Epstein-Barr virus-encoded interleukin-10. Blood 90:2390–2397

    CAS  PubMed  Google Scholar 

  • Zerby D, Chen CJ, Poon E, Lee D, Shiekhattar R, Lieberman PM (1999) The amino-terminal C/H1 domain of CREB binding protein mediates zta transcriptional activation of latent Epstein-Barr virus. Mol Cell Biol 19:1617–1626

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang Q, Hong Y, Dorsky D, Holley-Guthrie E, Zalani S, Elshiekh NA, Kiehl A, Le T, Kenney S (1996) Functional and physical interactions between the Epstein-Barr virus (EBV) proteins BZLF1 and BMRF1: effects on EBV transcription and lytic replication. J Virol 70:5131–5142

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang W, Ou J, Inagaki Y, Greenwel P, Ramirez F (2000) Synergistic cooperation between Sp1 and Smad3/Smad4 mediates transforming growth factor beta1 stimulation of alpha 2(I)-collagen (COL1A2) transcription. J Biol Chem 275:39237–39245

    Article  CAS  PubMed  Google Scholar 

  • zur Hausen H, O’Neil F, Freese U (1978) Persisting oncogenic herpesviruses induced by the tumor promoter TPA. Nature 272:373–375

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Division of Infectious Diseases, Yale University School of Medicine, New Haven, CT, 06520, USA

    Jessica McKenzie & Ayman El-Guindy

Authors
  1. Jessica McKenzie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ayman El-Guindy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ayman El-Guindy .

Editor information

Editors and Affiliations

  1. Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland

    Christian Münz

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

McKenzie, J., El-Guindy, A. (2015). Epstein-Barr Virus Lytic Cycle Reactivation. In: Münz, C. (eds) Epstein Barr Virus Volume 2. Current Topics in Microbiology and Immunology, vol 391. Springer, Cham. https://doi.org/10.1007/978-3-319-22834-1_8

Download citation

Publish with us

Policies and ethics

Search

Navigation