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Kwai Fung Hui, Po Ling Yeung, Kam Pui Tam, Alan Kwok Shing Chiang
Combination of suberoylanilide hydroxamic acid (SAHA) and bortezomib (SAHA/bortezomib) was shown to synergistically induce killing of lymphoblastoid cell lines (LCL) and Burkitt lymphoma (BL) of type III or Wp-restricted latency, both of which express EBNA3A, -3B and -3C proteins. We hypothesize that SAHA/bortezomib can counteract the survival functions conferred by the EBNA3 proteins. We tested the effect of SAHA/bortezomib on the survival of BL cell lines containing EBNA3A, -3B or -3C knockout EBV with or without the respective revertant EBNA3 genes...
May 18, 2018: Oncotarget
Christine T Styles, Kostas Paschos, Robert E White, Paul J Farrell
The Epstein-Barr nuclear antigen 3 (EBNA3) family of proteins, comprising EBNA3A, EBNA3B, and EBNA3C, play pivotal roles in the asymptomatic persistence and life-long latency of Epstein-Barr virus (EBV) in the worldwide human population. EBNA3-mediated transcriptional reprogramming of numerous host cell genes promotes in vitro B cell transformation and EBV persistence in vivo. Despite structural and sequence similarities, and evidence of substantial cooperative activity between the EBNA3 proteins, they perform quite different, often opposing functions...
March 17, 2018: Pathogens
Ana Cirac, Simon Stützle, Michael Dieckmeyer, Dinesh Adhikary, Andreas Moosmann, Nina Körber, Tanja Bauer, Klaus Witter, Henri-Jacques Delecluse, Uta Behrends, Josef Mautner
The Epstein-Barr virus (EBV) establishes lifelong infections in > 90% of the human population. Although contained as asymptomatic infection by the immune system in most individuals, EBV is associated with the pathogenesis of approximately 1.5% of all cancers in humans. Some of these EBV-associated tumors have been successfully treated by the infusion of virus-specific T-cell lines. Recent sequence analyses of a large number of viral isolates suggested that distinct EBV strains have evolved in different parts of the world...
April 2018: Cancer Immunology, Immunotherapy: CII
Quentin Bazot, Kostas Paschos, Martin J Allday
Epstein-Barr virus (EBV) establishes latent infection in human B cells and is associated with a wide range of cancers. The EBV nuclear antigen 3 (EBNA3) family proteins are critical for B cell transformation and function as transcriptional regulators. It is well established that EBNA3A and EBNA3C cooperate in the regulation of cellular genes. Here, we demonstrate that the gene STK39 is repressed only by EBNA3A. This is the first example of a gene regulated only by EBNA3A in EBV-transformed lymphoblastoid cell lines (LCLs) without the help of EBNA3C...
April 1, 2018: Journal of Virology
Fang Lu, Andreas Wiedmer, Kayla A Martin, Priyankara J M S Wickramasinghe, Andrew V Kossenkov, Paul M Lieberman
Epstein-Barr Virus (EBV) latency and its associated carcinogenesis are regulated by dynamic changes in DNA methylation of both virus and host genomes. We show here that the Ten-Eleven Translocation 2 (TET2) gene, implicated in hydroxymethylation and active DNA demethylation, is a key regulator of EBV latency type DNA methylation patterning. EBV latency types are defined by DNA methylation patterns that restrict expression of viral latency genes. We show that TET2 mRNA and protein expression correlate with the highly demethylated EBV type III latency program permissive for expression of EBNA2, EBNA3s, and LMP transcripts...
August 9, 2017: Journal of Virology
Christine T Styles, Quentin Bazot, Gillian A Parker, Robert E White, Kostas Paschos, Martin J Allday
Mature human B cells infected by Epstein-Barr virus (EBV) become activated, grow, and proliferate. If the cells are infected ex vivo, they are transformed into continuously proliferating lymphoblastoid cell lines (LCLs) that carry EBV DNA as extra-chromosomal episomes, express 9 latency-associated EBV proteins, and phenotypically resemble antigen-activated B-blasts. In vivo similar B-blasts can differentiate to become memory B cells (MBC), in which EBV persistence is established. Three related latency-associated viral proteins EBNA3A, EBNA3B, and EBNA3C are transcription factors that regulate a multitude of cellular genes...
August 2017: PLoS Biology
Samantha Correia, Anne Palser, Claudio Elgueta Karstegl, Jaap M Middeldorp, Octavia Ramayanti, Jeffrey I Cohen, Allan Hildesheim, Maria Dolores Fellner, Joelle Wiels, Robert E White, Paul Kellam, Paul J Farrell
Viral gene sequences from an enlarged set of about 200 Epstein-Barr virus (EBV) strains, including many primary isolates, have been used to investigate variation in key viral genetic regions, particularly LMP1, Zp, gp350, EBNA1, and the BART microRNA (miRNA) cluster 2. Determination of type 1 and type 2 EBV in saliva samples from people from a wide range of geographic and ethnic backgrounds demonstrates a small percentage of healthy white Caucasian British people carrying predominantly type 2 EBV. Linkage of Zp and gp350 variants to type 2 EBV is likely to be due to their genes being adjacent to the EBNA3 locus, which is one of the major determinants of the type 1/type 2 distinction...
August 1, 2017: Journal of Virology
Kostas Paschos, Quentin Bazot, Guiyi Ho, Gillian A Parker, Jonathan Lees, Geraint Barton, Martin J Allday
ChIP-seq performed on lymphoblastoid cell lines (LCLs), expressing epitope-tagged EBNA3A, EBNA3B or EBNA3C from EBV-recombinants, revealed important principles of EBNA3 binding to chromatin. When combined with global chromatin looping data, EBNA3-bound loci were found to have a singular character, each directly associating with either EBNA3-repressed or EBNA3-activated genes, but not with both. EBNA3A and EBNA3C showed significant association with repressed and activated genes. Significant direct association for EBNA3B loci could only be shown with EBNA3B-repressed genes...
March 17, 2017: Nucleic Acids Research
Lijuan Hu, Zhirui Lin, Yanheng Wu, Juqin Dong, Bo Zhao, Yanbing Cheng, Peiyu Huang, Lihua Xu, Tianliang Xia, Dan Xiong, Hongbo Wang, Manzhi Li, Ling Guo, Elliott Kieff, Yixin Zeng, Qian Zhong, Musheng Zeng
The latent expression pattern of Epstein-Barr Virus (EBV) genes in nasopharyngeal carcinoma (NPC) has been extensively investigated, and the expression of several lytic genes in NPC has been reported. However, comprehensive information through EBV transcriptome analysis in NPC is limited. We performed paired-end RNA-seq to systematically and comprehensively characterize the expression of EBV genes in NPC tissue and C666-1 NPC cell line, which consistently carries EBV. In addition to the transcripts restricted to type II latency infection, the type III latency EBNA3s genes and a substantial number of lytic genes, such as BZLF1, BRLF1, and BMRF1, were detected through RNA-seq and were further verified in C666-1 cells and NPC tissue through realtime PCR...
March 2016: Frontiers of Medicine
Hem Chandra Jha, Shuvomoy Banerjee, Erle S Robertson
Worldwide, one fifth of cancers in the population are associated with viral infections. Among them, gammaherpesvirus, specifically HHV4 (EBV) and HHV8 (KSHV), are two oncogenic viral agents associated with a large number of human malignancies. In this review, we summarize the current understanding of the molecular mechanisms related to EBV and KSHV infection and their ability to induce cellular transformation. We describe their strategies for manipulating major cellular systems through the utilization of cell cycle, apoptosis, immune modulation, epigenetic modification, and altered signal transduction pathways, including NF-kB, Notch, Wnt, MAPK, TLR, etc...
2016: Pathogens
Anqi Wang, Rene Welch, Bo Zhao, Tram Ta, Sündüz Keleş, Eric Johannsen
UNLABELLED: Latent infection of B lymphocytes by Epstein-Barr virus (EBV) in vitro results in their immortalization into lymphoblastoid cell lines (LCLs); this latency program is controlled by the EBNA2 viral transcriptional activator, which targets promoters via RBPJ, a DNA binding protein in the Notch signaling pathway. Three other EBNA3 proteins (EBNA3A, EBNA3B, and EBNA3C) interact with RBPJ to regulate cell gene expression. The mechanism by which EBNAs regulate different genes via RBPJ remains unclear...
December 30, 2015: Journal of Virology
Martin J Allday, Quentin Bazot, Robert E White
Epstein-Barr virus nuclear antigens EBNA3A , EBNA3B and EBNA3C are a family of three large latency-associated proteins expressed in B cells induced to proliferate by the virus. Together with the other nuclear antigens (EBNA-LP, EBNA2 and EBNA1), they are expressed from a polycistronic transcription unit that is probably unique to B cells. However, compared with the other EBNAs, hitherto the EBNA3 proteins were relatively neglected and their roles in EBV biology rather poorly understood. In recent years, powerful new technologies have been used to show that these proteins are central to the latency of EBV in B cells, playing major roles in reprogramming the expression of host genes affecting cell proliferation, survival, differentiation and immune surveillance...
2015: Current Topics in Microbiology and Immunology
Makoto Ohashi, Amy M Holthaus, Michael A Calderwood, Chiou-Yan Lai, Bryan Krastins, David Sarracino, Eric Johannsen
The Epstein-Barr virus (EBV) nuclear proteins EBNA3A, EBNA3B, and EBNA3C interact with the cell DNA binding protein RBPJ and regulate cell and viral genes. Repression of the CDKN2A tumor suppressor gene products p16(INK4A) and p14(ARF) by EBNA3A and EBNA3C is critical for EBV mediated transformation of resting B lymphocytes into immortalized lymphoblastoid cell lines (LCLs). To define the composition of endogenous EBNA3 protein complexes, we generated lymphoblastoid cell lines (LCLs) expressing flag-HA tagged EBNA3A, EBNA3B, or EBNA3C and used tandem affinity purification to isolate each EBNA3 complex...
April 2015: PLoS Pathogens
Anne L Palser, Nicholas E Grayson, Robert E White, Craig Corton, Samantha Correia, Mohammed M Ba Abdullah, Simon J Watson, Matthew Cotten, John R Arrand, Paul G Murray, Martin J Allday, Alan B Rickinson, Lawrence S Young, Paul J Farrell, Paul Kellam
UNLABELLED: Epstein-Barr virus (EBV) infects most of the world's population and is causally associated with several human cancers, but little is known about how EBV genetic variation might influence infection or EBV-associated disease. There are currently no published wild-type EBV genome sequences from a healthy individual and very few genomes from EBV-associated diseases. We have sequenced 71 geographically distinct EBV strains from cell lines, multiple types of primary tumor, and blood samples and the first EBV genome from the saliva of a healthy carrier...
May 2015: Journal of Virology
Raija K Ahmed, Thomas Poiret, Aditya Ambati, Lalit Rane, Mats Remberger, Birgitta Omazic, Nalini K Vudattu, Jacek Winiarski, Ingemar Ernberg, Rebecca Axelsson-Robertson, Isabelle Magalhaes, Chiara Castelli, Olle Ringden, Markus Maeurer
Human TCRαβ(+) CD4(-)CD8(-) double-negative (DN) T cells represent a minor subset in peripheral blood, yet are important in infectious diseases and autoimmune responses. We examined the frequency of DN T cells in 17 patients after allogeneic hematopoietic stem cell transplantation (aHSCT) at 1, 2, 3, 6, and 12 months post-aHSCT and show that these cells increase early after aHSCT and decrease with time after aHSCT. DN T cells reside in the terminally differentiated effector (CD45RA(+)CCR7(-)) T-cell population and are polyclonal, determined by T-cell receptor Vβ CDR3 analysis...
October 2014: Journal of Immunotherapy
Quentin Bazot, Thibaut Deschamps, Lionel Tafforeau, Maha Siouda, Pascal Leblanc, Marie L Harth-Hertle, Chantal Rabourdin-Combe, Vincent Lotteau, Bettina Kempkes, Massimo Tommasino, Henri Gruffat, Evelyne Manet
The Epstein-Barr virus (EBV) nuclear antigen 3 family of protein is critical for the EBV-induced primary B-cell growth transformation process. Using a yeast two-hybrid screen we identified 22 novel cellular partners of the EBNA3s. Most importantly, among the newly identified partners, five are known to play direct and important roles in transcriptional regulation. Of these, the Myc-interacting zinc finger protein-1 (MIZ-1) is a transcription factor initially characterized as a binding partner of MYC. MIZ-1 activates the transcription of a number of target genes including the cell cycle inhibitor CDKN2B...
September 2014: Nucleic Acids Research
Yingying Wang, Lamia Aïssi-Rothe, Jean Marc Virion, Marcelo De Carvalho Bittencourt, Neslihan Ulas, Sandra Audonnet, Alexandra Salmon, Laurence Clement, Veronique Venard, Helène Jeulin, Jean-François Stoltz, Veronique Decot, Danièle Bensoussan
BACKGROUND: Epstein-Barr virus (EBV) infection is a major cause of morbidity following hematopoietic stem cell transplantation. EBV-infected B cells may not respond to rituximab treatment and may lead to a life-threatening post-transplantation lymphoproliferative disorder. Adoptive cellular immunotherapy using EBV-lymphoblastoid cell lines (LCL) as stimulating antigen has proved effective in restoring specific immunity. However, EBV presents several immunodominant antigens, and developing a swift and effective clinical-grade immunotherapy relies on the definition of a Good Manufacturing Practices (GMP) universal stimulating antigen...
January 2014: Cytotherapy
Sandra A Calarota, Antonella Chiesa, Paola Zelini, Giuditta Comolli, Lorenzo Minoli, Fausto Baldanti
Approaches to evaluate T-cell responses to Epstein-Barr virus (EBV) include enzyme-linked immunospot (ELISPOT), which quantifies cells capable of immediate interferon-γ secretion upon antigen stimulation. However, evaluation of expandable EBV-specific memory T cells in an ELISPOT format has not been described previously. We quantified EBV-specific T-cell precursors with high proliferative capacity by using a peptide-based cultured interferon-γ ELISPOT assay. Standard and cultured ELISPOT responses to overlapping peptide pools (15-mers overlapping by 11 amino acids) covering the lytic (BZLF1 and BMRF1) and latent (EBNA1, EBNA3a, EBNA3b, EBNA3c, LMP1 and LMP2) EBV proteins were evaluated in 20 healthy subjects with remote EBV infection and, for comparison, in four solid organ transplant recipients...
August 2013: Immunology
Yoshinori Ito, Yoshiki Kawamura, Seiko Iwata, Jun-Ichi Kawada, Tetsushi Yoshikawa, Hiroshi Kimura
Epstein-Barr virus (EBV) is the most common infectious cause of non-genetic hemophagocytic lymphohistiocytosis (HLH). To investigate EBV-infected lymphocytes and immune dysfunction in EBV-associated HLH, blood samples from a 6-year-old boy were longitudinally analyzed using molecular techniques. EBV-positive lymphocytes were detected as CD5(+) , CD8(+) , and/or HLA DR(+) lymphocytes on Day 25 of the disease, mostly disappearing thereafter. CD8(+) cells specific for lytic antigen BRLF1 were detected, but cells specific for latent antigens EBNA3 and LMP2 were not...
February 2013: Pediatric Blood & Cancer
Raymond J Ning, Xue Q Xu, Kwok H Chan, Alan K S Chiang
T cells simultaneously producing multiple cytokines and possessing cytotoxic capacity termed polyfunctional cells (PFCs) are increasingly recognized as the immune correlate of protection against pathogenic viruses. We investigated co-expression of four cytokines (interferon-γ, macrophage inflammatory protein 1-α, tumour necrosis factor-α and interleukin-2) and degranulation capacity (CD107a surface expression) of Epstein-Barr virus (EBV) -specific CD4(+) and CD8(+) T cells upon stimulation by overlapping peptides of EBV lytic (BZLF1) and latent (EBNA1, EBNA3 and LMP2) proteins, in 20 healthy Chinese long-term carriers...
October 2011: Immunology
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