{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T23:48:09Z","timestamp":1792021689227,"version":"4.4.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013610","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000}}],"reference-count":89,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE025994"],"award-info":[{"award-number":["R01DE025994"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["U01CA275306"],"award-info":[{"award-number":["U01CA275306"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["T32CA009111"],"award-info":[{"award-number":["T32CA009111"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["F31DE033216"],"award-info":[{"award-number":["F31DE033216"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Epstein-Barr virus (EBV) is associated with multiple malignancies including Burkitt lymphoma (BL), Hodgkin\u2019s lymphomas, nasopharyngeal carcinomas (NPC), and gastric cancers. Canonically, EBV positive tumors display latent gene expression programs that are difficult to target pharmacologically. To overcome this hurdle, lytic reactivation therapies have been developed based on HDAC inhibition with limited mechanistic studies. We therefore characterized the impact of pan-HDAC inhibitor, panobinostat, and class I HDAC inhibitor, nanatinostat, on the growth, survival, and lytic reactivation of four EBV-positive cell lines: P3HR1-ZHT BL, Jijoye BL, IBL-1 immunoblastic lymphoma, and\n                    <jats:italic>de novo<\/jats:italic>\n                    infection derived lymphoblastoid cell lines (LCL). All lines were sensitive, enabling us to define ranges of sensitivity within which to use single cell approaches to assess early EBV lytic gene expression, cell cycle state, and apoptosis. We observed that each EBV-positive model of malignancy responded uniquely to the same HDAC inhibitors and that lytic reactivation was successful in only a small percentage of the cell population. To elucidate the potential role of host factors in preventing successful lytic reactivation, we performed single-cell RNA sequencing on the P3HR1-ZHT BL line treated with the HDAC inhibitor panobinostat. We observed that abortive lytic cells, or cells that do not successfully progress through the lytic cycle, upregulated genes downstream of NF-\u03baB activity. Additionally, genes involved in immune signaling including the CD137\/CD137L signaling axis, were upregulated in abortive lytic cells. Functional validation through a Cas9-RNP approach revealed that the CD137 receptor is indeed involved in preventing successful lytic reactivation. These data have important implications for how we approach oncolytic therapies for EBV-associated malignancies.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013610","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T17:47:56Z","timestamp":1774288076000},"page":"e1013610","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Single-cell profiling of HDAC inhibitor-induced EBV lytic heterogeneity defines abortive and refractory states in B lymphoblasts"],"prefix":"10.1371","volume":"22","author":[{"given":"Lauren E.","family":"Haynes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley P.","family":"Barry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2964-1907","authenticated-orcid":true,"given":"Micah A.","family":"Luftig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"issue":"8","key":"ppat.1013610.ref001","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2020-037505","article-title":"Global and regional incidence, mortality and disability-adjusted life-years for Epstein-Barr virus-attributable malignancies, 1990\u20132017","volume":"10","author":"G Khan","year":"2020","journal-title":"BMJ Open"},{"issue":"3","key":"ppat.1013610.ref002","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/S1074-7613(00)80622-6","article-title":"EBV persistence in memory B cells in vivo","volume":"9","author":"GJ Babcock","year":"1998","journal-title":"Immunity"},{"issue":"6","key":"ppat.1013610.ref003","article-title":"Clinical characteristics and prognostic significance of EBER positivity in diffuse large B-cell lymphoma: A meta-analysis","volume":"13","author":"X Gao","year":"2018","journal-title":"PLoS One"},{"key":"ppat.1013610.ref004","doi-asserted-by":"crossref","first-page":"713","DOI":"10.3389\/fonc.2019.00713","article-title":"The Global Landscape of EBV-Associated Tumors","volume":"9","author":"C Shannon-Lowe","year":"2019","journal-title":"Front Oncol"},{"issue":"2","key":"ppat.1013610.ref005","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1128\/JVI.79.2.1296-1307.2005","article-title":"Terminal differentiation into plasma cells initiates the replicative cycle of Epstein-Barr virus in vivo","volume":"79","author":"LL Laichalk","year":"2005","journal-title":"J Virol"},{"issue":"1","key":"ppat.1013610.ref006","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/ijc.2910350107","article-title":"A re-examination of the Epstein-Barr virus carrier state in healthy seropositive individuals","volume":"35","author":"QY Yao","year":"1985","journal-title":"Int J 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Tikhmyanova","year":"2014","journal-title":"ACS Chem Biol"},{"issue":"1","key":"ppat.1013610.ref012","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1002\/ijc.29698","article-title":"Inhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir","volume":"138","author":"KF Hui","year":"2016","journal-title":"Int J Cancer"},{"key":"ppat.1013610.ref013","first-page":"55","article-title":"Theodore E. Woodward Award: development of novel, EBV-targeted therapies for EBV-positive tumors","volume":"117","author":"S Kenney","year":"2006","journal-title":"Trans Am Clin Climatol Assoc"},{"issue":"20","key":"ppat.1013610.ref014","first-page":"5781","article-title":"Activation of lytic Epstein-Barr virus (EBV) infection by radiation and sodium butyrate in vitro and in vivo: a potential method for treating EBV-positive malignancies","volume":"60","author":"EM Westphal","year":"2000","journal-title":"Cancer Res"},{"issue":"81","key":"ppat.1013610.ref015","article-title":"Viral-targeted strategies against EBV-associated lymphoproliferative diseases","volume":"9","author":"KF Hui","year":"2019","journal-title":"Frontiers in Oncology"},{"issue":"8","key":"ppat.1013610.ref016","doi-asserted-by":"crossref","first-page":"2142","DOI":"10.3390\/cancers12082142","article-title":"Lytic Induction Therapy against Epstein-Barr Virus-Associated Malignancies: Past, Present, and 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Piekarz","year":"2011","journal-title":"Blood"},{"issue":"4","key":"ppat.1013610.ref020","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a018713","article-title":"Erasers of histone acetylation: the histone deacetylase enzymes","volume":"6","author":"E Seto","year":"2014","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"1","key":"ppat.1013610.ref021","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.molcel.2010.01.042","article-title":"Highly compacted chromatin formed in vitro reflects the dynamics of transcription activation in vivo","volume":"38","author":"G Li","year":"2010","journal-title":"Mol Cell"},{"issue":"37","key":"ppat.1013610.ref022","doi-asserted-by":"crossref","first-page":"5541","DOI":"10.1038\/sj.onc.1210620","article-title":"Histone deacetylase inhibitors: molecular mechanisms of action","volume":"26","author":"WS Xu","year":"2007","journal-title":"Oncogene"},{"issue":"20","key":"ppat.1013610.ref023","doi-asserted-by":"crossref","first-page":"3885","DOI":"10.1007\/s00018-014-1656-6","article-title":"Histone deacetylase inhibitors and cell death","volume":"71","author":"J Zhang","year":"2014","journal-title":"Cell Mol Life Sci"},{"issue":"46","key":"ppat.1013610.ref024","doi-asserted-by":"crossref","first-page":"20003","DOI":"10.1073\/pnas.1013754107","article-title":"Selective inhibition of histone deacetylase 6 (HDAC6) induces DNA damage and sensitizes transformed cells to anticancer agents","volume":"107","author":"M Namdar","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"25","key":"ppat.1013610.ref025","doi-asserted-by":"crossref","first-page":"4218","DOI":"10.2174\/092986712802884286","article-title":"The synergistic effects of DNA-targeted chemotherapeutics and histone deacetylase inhibitors as therapeutic strategies for cancer treatment","volume":"19","author":"M Stiborov\u00e1","year":"2012","journal-title":"Curr Med Chem"},{"issue":"20","key":"ppat.1013610.ref026","doi-asserted-by":"crossref","first-page":"6339","DOI":"10.1182\/bloodadvances.2023010330","article-title":"Targeted therapy with nanatinostat and valganciclovir in recurrent EBV-positive lymphoid malignancies: a phase 1b\/2 study","volume":"7","author":"B Haverkos","year":"2023","journal-title":"Blood Adv"},{"key":"ppat.1013610.ref027","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.semcancer.2014.01.002","article-title":"Regulation of the latent-lytic switch in Epstein-Barr virus","volume":"26","author":"SC Kenney","year":"2014","journal-title":"Semin Cancer Biol"},{"key":"ppat.1013610.ref028","doi-asserted-by":"crossref","DOI":"10.1017\/CBO9780511545313.026","article-title":"Reactivation and lytic replication of EBV.","volume-title":"Human herpesviruses: biology, therapy, and immunoprophylaxis","author":"SC Kenney","year":"2007"},{"issue":"1","key":"ppat.1013610.ref029","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/0042-6822(91)90778-A","article-title":"Formation of intranuclear replication compartments of Epstein-Barr virus with redistribution of BZLF1 and BMRF1 gene products","volume":"185","author":"S Takagi","year":"1991","journal-title":"Virology"},{"issue":"20","key":"ppat.1013610.ref030","doi-asserted-by":"crossref","first-page":"10282","DOI":"10.1128\/JVI.76.20.10282-10289.2002","article-title":"Promoter sequences required for reactivation of Epstein-Barr virus from latency","volume":"76","author":"UK Binn\u00e9","year":"2002","journal-title":"J Virol"},{"issue":"6","key":"ppat.1013610.ref031","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1005718","article-title":"An Epstein-Barr Virus-Encoded Protein Complex Requires an Origin of Lytic Replication In Cis to Mediate Late Gene Transcription","volume":"12","author":"R Djavadian","year":"2016","journal-title":"PLoS Pathog"},{"issue":"21","key":"ppat.1013610.ref032","doi-asserted-by":"crossref","first-page":"12825","DOI":"10.1128\/JVI.02139-14","article-title":"Epstein-Barr virus late gene transcription depends on the assembly of a virus-specific preinitiation complex","volume":"88","author":"V Aubry","year":"2014","journal-title":"J Virol"},{"issue":"11","key":"ppat.1013610.ref033","doi-asserted-by":"crossref","first-page":"6023","DOI":"10.1128\/JVI.00159-12","article-title":"The Epstein-Barr virus BcRF1 gene product is a TBP-like protein with an essential role in late gene expression","volume":"86","author":"H Gruffat","year":"2012","journal-title":"J Virol"},{"issue":"7","key":"ppat.1013610.ref034","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1128\/AAC.45.7.2082-2091.2001","article-title":"Induction of Epstein-Barr virus kinases to sensitize tumor cells to nucleoside analogues","volume":"45","author":"SM Moore","year":"2001","journal-title":"Antimicrob Agents Chemother"},{"key":"ppat.1013610.ref035","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1099\/0022-1317-66-9-1931","article-title":"Chromatin structure of Epstein-Barr virus","author":"PJ Dyson","year":"1985","journal-title":"J Gen Virol"},{"issue":"2","key":"ppat.1013610.ref036","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1128\/JVI.74.2.710-720.2000","article-title":"Histone acetylation and reactivation of Epstein-Barr virus from latency","volume":"74","author":"PJ Jenkins","year":"2000","journal-title":"J Virol"},{"issue":"5","key":"ppat.1013610.ref037","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.1128\/JVI.01602-10","article-title":"Interplay between PKC\u03b4 and Sp1 on histone deacetylase inhibitor-mediated Epstein-Barr virus reactivation","volume":"85","author":"P-F Tsai","year":"2011","journal-title":"J Virol"},{"key":"ppat.1013610.ref038","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1099\/vir.0.83533-0","article-title":"Essential role of PKCdelta in histone deacetylase inhibitor-induced Epstein-Barr virus reactivation in nasopharyngeal carcinoma cells","volume":"89","author":"H-H Lee","year":"2008","journal-title":"J Gen Virol"},{"issue":"2","key":"ppat.1013610.ref039","article-title":"Reactivation of Epstein-Barr Virus from Latency Involves Increased RNA Polymerase Activity at CTCF Binding Sites on the Viral Genome","volume":"97","author":"LEM Dunn","year":"2023","journal-title":"J Virol"},{"issue":"5","key":"ppat.1013610.ref040","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1128\/jvi.1.5.1045-1051.1967","article-title":"Immunofluorescence and herpes-type virus particles in the P3HR-1 Burkitt lymphoma cell line","volume":"1","author":"Y Hinuma","year":"1967","journal-title":"J 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reprogrammed, and host shutoff states by lytic progression","volume":"20","author":"ED SoRelle","year":"2024","journal-title":"PLoS Pathog"},{"issue":"16","key":"ppat.1013610.ref044","doi-asserted-by":"crossref","first-page":"8041","DOI":"10.1128\/JVI.00382-09","article-title":"Negative autoregulation of Epstein-Barr virus (EBV) replicative gene expression by EBV SM protein","volume":"83","author":"D Verma","year":"2009","journal-title":"J Virol"},{"issue":"1","key":"ppat.1013610.ref045","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/s41467-021-27729-z","article-title":"Zero-preserving imputation of single-cell RNA-seq data","volume":"13","author":"GC Linderman","year":"2022","journal-title":"Nat Commun"},{"issue":"1","key":"ppat.1013610.ref046","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"S Jin","year":"2021","journal-title":"Nat Commun"},{"issue":"3","key":"ppat.1013610.ref047","first-page":"549","article-title":"The Epstein-Barr virus latent membrane protein-1 (LMP1) mediates activation of NF-kappa B and cell surface phenotype via two effector regions in its carboxy-terminal cytoplasmic domain","volume":"10","author":"DS Huen","year":"1995","journal-title":"Oncogene"},{"issue":"19","key":"ppat.1013610.ref048","doi-asserted-by":"crossref","first-page":"9150","DOI":"10.1073\/pnas.90.19.9150","article-title":"Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation","volume":"90","author":"KM Kaye","year":"1993","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"ppat.1013610.ref049","article-title":"MYC Controls the Epstein-Barr Virus Lytic Switch","volume":"78","author":"R Guo","year":"2020","journal-title":"Mol Cell"},{"issue":"2","key":"ppat.1013610.ref050","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1128\/JVI.01745-09","article-title":"Upregulation of STAT3 marks Burkitt lymphoma cells refractory to Epstein-Barr virus lytic cycle induction by HDAC inhibitors","volume":"84","author":"D Daigle","year":"2010","journal-title":"J Virol"},{"issue":"9","key":"ppat.1013610.ref051","doi-asserted-by":"crossref","first-page":"5002","DOI":"10.1128\/JVI.00121-15","article-title":"Cellular STAT3 functions via PCBP2 to restrain Epstein-Barr Virus lytic activation in B lymphocytes","volume":"89","author":"S Koganti","year":"2015","journal-title":"J Virol"},{"issue":"4","key":"ppat.1013610.ref052","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1006\/bbrc.2001.6067","article-title":"NF-\u03baB activation for constitutive expression of VCAM-1 and ICAM-1 on B lymphocytes and plasma cells","volume":"289","author":"YF Xia","year":"2001","journal-title":"Biochemical and Biophysical Research Communications"},{"issue":"10","key":"ppat.1013610.ref053","doi-asserted-by":"crossref","first-page":"2631","DOI":"10.1002\/eji.1830231037","article-title":"Molecular cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor","volume":"23","author":"RG Goodwin","year":"1993","journal-title":"Eur J Immunol"},{"issue":"3","key":"ppat.1013610.ref054","doi-asserted-by":"crossref","first-page":"771","DOI":"10.4049\/jimmunol.150.3.771","article-title":"Inducible T cell antigen 4-1BB. Analysis of expression and function","volume":"150","author":"KE Pollok","year":"1993","journal-title":"J Immunol"},{"issue":"3","key":"ppat.1013610.ref055","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1006\/bbrc.1997.8016","article-title":"Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-\u03baB","volume":"242","author":"IK Jang","year":"1998","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"ppat.1013610.ref056","doi-asserted-by":"crossref","first-page":"968360","DOI":"10.3389\/fonc.2022.968360","article-title":"4-1BB: A promising target for cancer immunotherapy","volume":"12","author":"AMJ Kim","year":"2022","journal-title":"Front Oncol"},{"issue":"5","key":"ppat.1013610.ref057","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0064425","article-title":"CD137 is induced by the CD40 signal on chronic lymphocytic leukemia B cells and transduces the survival signal via NF-\u03baB activation","volume":"8","author":"Y Nakaima","year":"2013","journal-title":"PLoS One"},{"issue":"2","key":"ppat.1013610.ref058","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1097\/PAS.0b013e318268c6ea","article-title":"CD137 ligand is expressed in primary and secondary lymphoid follicles and in B-cell lymphomas: diagnostic and therapeutic implications","volume":"37","author":"S Zhao","year":"2013","journal-title":"Am J Surg Pathol"},{"issue":"11","key":"ppat.1013610.ref059","doi-asserted-by":"crossref","first-page":"2697","DOI":"10.1080\/10428194.2019.1607330","article-title":"Epstein-Barr virus-encoded LMP1 induces ectopic CD137 expression on Hodgkin and Reed-Sternberg cells via the PI3K-AKT-mTOR pathway","volume":"60","author":"SP Aravinth","year":"2019","journal-title":"Leuk Lymphoma"},{"issue":"11","key":"ppat.1013610.ref060","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0112564","article-title":"CD137 expression is induced by Epstein-Barr virus infection through LMP1 in T or NK cells and mediates survival promoting signals","volume":"9","author":"M Yoshimori","year":"2014","journal-title":"PLoS One"},{"issue":"4","key":"ppat.1013610.ref061","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1009117","article-title":"Highly efficient CRISPR-Cas9-mediated gene knockout in primary human B cells for functional genetic studies of Epstein-Barr virus infection","volume":"17","author":"E Akidil","year":"2021","journal-title":"PLoS Pathog"},{"issue":"20","key":"ppat.1013610.ref062","doi-asserted-by":"crossref","first-page":"3918","DOI":"10.1093\/nar\/28.20.3918","article-title":"Activation of the BRLF1 promoter and lytic cycle of Epstein-Barr virus by histone acetylation","volume":"28","author":"LK Chang","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"ppat.1013610.ref063","doi-asserted-by":"crossref","DOI":"10.3389\/fmicb.2016.02129","article-title":"Trim5\u03b1 promotes ubiquitination of Rta from Epstein\u2013Barr virus to 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p53 in histone deacetylase inhibitor-induced Epstein-Barr virus Zta expression","volume":"82","author":"S-S Chang","year":"2008","journal-title":"J Virol"},{"issue":"4","key":"ppat.1013610.ref068","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.chom.2011.08.013","article-title":"Conserved herpesvirus kinases target the DNA damage response pathway and TIP60 histone acetyltransferase to promote virus replication","volume":"10","author":"R Li","year":"2011","journal-title":"Cell Host Microbe"},{"issue":"12","key":"ppat.1013610.ref069","article-title":"Phosphoproteomic Profiling Reveals Epstein-Barr Virus Protein Kinase Integration of DNA Damage Response and Mitotic Signaling","volume":"11","author":"R Li","year":"2015","journal-title":"PLoS Pathog"},{"issue":"9","key":"ppat.1013610.ref070","doi-asserted-by":"crossref","first-page":"8156","DOI":"10.1074\/jbc.M411405200","article-title":"Epstein-Barr virus lytic replication elicits ATM checkpoint signal transduction while providing an S-phase-like cellular environment","volume":"280","author":"A Kudoh","year":"2005","journal-title":"J Biol Chem"},{"issue":"7","key":"ppat.1013610.ref071","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1016\/j.celrep.2017.04.062","article-title":"A Temporal Proteomic Map of Epstein-Barr Virus Lytic Replication in B Cells","volume":"19","author":"I Ersing","year":"2017","journal-title":"Cell Rep"},{"issue":"12","key":"ppat.1013610.ref072","doi-asserted-by":"crossref","first-page":"3445","DOI":"10.1016\/j.celrep.2017.11.071","article-title":"B Cell Receptor Activation and Chemical Induction Trigger Caspase-Mediated Cleavage of PIAS1 to Facilitate Epstein-Barr Virus Reactivation","volume":"21","author":"K Zhang","year":"2017","journal-title":"Cell Rep"},{"issue":"1","key":"ppat.1013610.ref073","article-title":"Interferon regulatory factor 8 regulates caspase-1 expression to facilitate Epstein-Barr virus reactivation in response to B cell receptor stimulation and chemical induction","volume":"14","author":"D-W Lv","year":"2018","journal-title":"PLoS Pathog"},{"issue":"3","key":"ppat.1013610.ref074","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1073\/pnas.1919133117","article-title":"A promiscuous inflammasome sparks replication of a common tumor virus","volume":"117","author":"EM Burton","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ppat.1013610.ref075","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1099\/vir.0.18845-0","article-title":"A novel function for the Epstein-Barr virus transcription factor EB1\/Zta: induction of transcription of the hIL-10 gene","volume":"84","author":"S Mahot","year":"2003","journal-title":"J Gen Virol"},{"issue":"23","key":"ppat.1013610.ref076","doi-asserted-by":"crossref","first-page":"12362","DOI":"10.1128\/JVI.00712-10","article-title":"The Epstein-Barr virus BZLF1 protein inhibits tumor necrosis factor receptor 1 expression through effects on cellular C\/EBP proteins","volume":"84","author":"JA Bristol","year":"2010","journal-title":"J Virol"},{"issue":"1","key":"ppat.1013610.ref077","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1128\/JVI.78.1.544-549.2004","article-title":"Epstein-Barr virus immediate-early protein BZLF1 inhibits tumor necrosis factor alpha-induced signaling and apoptosis by downregulating tumor necrosis factor receptor 1","volume":"78","author":"TE Morrison","year":"2004","journal-title":"Journal of Virology"},{"issue":"21","key":"ppat.1013610.ref078","doi-asserted-by":"crossref","first-page":"11438","DOI":"10.1128\/JVI.01762-13","article-title":"Signal transducer and activator of transcription 3 limits Epstein-Barr virus lytic activation in B lymphocytes","volume":"87","author":"ER Hill","year":"2013","journal-title":"J Virol"},{"key":"ppat.1013610.ref079","article-title":"Signal transducer and activator of transcription 3 (STAT3) controls susceptibility to Epstein-Barr virus reactivation in B cells","volume":"7","author":"ER Hill","year":"2012","journal-title":"Infect Agents Cancer"},{"issue":"8","key":"ppat.1013610.ref080","doi-asserted-by":"crossref","first-page":"5000","DOI":"10.1128\/JVI.77.8.5000-5007.2003","article-title":"Latent membrane protein 1 inhibits Epstein-Barr virus lytic cycle induction and progress via different mechanisms","volume":"77","author":"S Prince","year":"2003","journal-title":"J Virol"},{"issue":"12","key":"ppat.1013610.ref081","doi-asserted-by":"crossref","first-page":"5088","DOI":"10.1111\/cas.15152","article-title":"A STING inhibitor suppresses EBV-induced B cell transformation and lymphomagenesis","volume":"112","author":"S Miyagi","year":"2021","journal-title":"Cancer Sci"},{"issue":"23","key":"ppat.1013610.ref082","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.01085-19","article-title":"Know Thyself: RIG-I-Like Receptor Sensing of DNA Virus Infection","volume":"93","author":"Y Zhao","year":"2019","journal-title":"J Virol"},{"issue":"6","key":"ppat.1013610.ref083","doi-asserted-by":"crossref","first-page":"183","DOI":"10.3390\/microorganisms7060183","article-title":"Epstein\u2013Barr Virus and Innate Immunity: Friends or Foes?","volume":"7","author":"S Jangra","year":"2019","journal-title":"Microorganisms"},{"issue":"18","key":"ppat.1013610.ref084","doi-asserted-by":"crossref","first-page":"4207","DOI":"10.1038\/sj.emboj.7601314","article-title":"EB virus-encoded RNAs are recognized by RIG-I and activate signaling to induce type I IFN","volume":"25","author":"M Samanta","year":"2006","journal-title":"EMBO J"},{"issue":"6","key":"ppat.1013610.ref085","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.3390\/biomedicines10061250","article-title":"NF-\u03baB: A double-edged sword controlling inflammation","volume":"10","author":"D Liu","year":"2022","journal-title":"Biomedicines"},{"issue":"2","key":"ppat.1013610.ref086","article-title":"Leveraging the interconnected unfolded protein response and NLRP3 inflammasome pathways to reactivate Epstein-Barr virus in diffuse large B-cell lymphomas","volume":"7","author":"H Xu","year":"2025","journal-title":"NAR Cancer"},{"issue":"13","key":"ppat.1013610.ref087","article-title":"An Epstein-Barr virus protein interaction map reveals NLRP3 inflammasome evasion via MAVS UFMylation","volume":"83","author":"SPT Yiu","year":"2023","journal-title":"Mol Cell"},{"key":"ppat.1013610.ref088","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.02618","article-title":"CD137 (4-1BB) signalosome: complexity is a matter of TRAFs","volume":"9","author":"JM Zapata","year":"2018","journal-title":"Frontiers in Immunology"},{"issue":"2","key":"ppat.1013610.ref089","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.cyto.2007.03.005","article-title":"Three is better than one: pre-ligand receptor assembly in the regulation of TNF receptor signaling","volume":"37","author":"FK-M 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