Oncogenic Properties of the EBV ZEBRA Protein

Epstein Barr Virus (EBV) is one of the most common human herpesviruses. After primary infection, it can persist in the host throughout their lifetime in a latent form, from which it can reactivate following specific stimuli. EBV reactivation is triggered by transcriptional transactivator proteins ZEBRA (also known as Z, EB-1, Zta or BZLF1) and RTA (also known as BRLF1). Here we discuss the structural and functional features of ZEBRA, its role in oncogenesis and its possible implication as a prognostic or diagnostic marker. Modulation of host gene expression by ZEBRA can deregulate the immune surveillance, allow the immune escape, and favor tumor progression. It also interacts with host proteins, thereby modifying their functions. ZEBRA is released into the bloodstream by infected cells and can potentially penetrate any cell through its cell-penetrating domain; therefore, it can also change the fate of non-infected cells. The features of ZEBRA described in this review outline its importance in EBV-related malignancies.

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Role of BamHI-A Rightward Frame 1 in Epstein–Barr Virus-Associated Epithelial Malignancies

Biology ◽

10.3390/biology9120461 ◽

2020 ◽

Vol 9 (12) ◽

pp. 461

Author(s):

Rancés Blanco ◽

Francisco Aguayo

Keyword(s):

Epstein Barr Virus ◽

Immune Escape ◽

Tumor Formation ◽

Host Proteins ◽

Barr Virus ◽

Functional Aspects ◽

Infected Cells ◽

Epstein Barr ◽

Apoptotic Effects

Epstein–Barr virus (EBV) infection is associated with a subset of both lymphoid and epithelial malignancies. During the EBV latency program, some viral products involved in the malignant transformation of infected cells are expressed. Among them, the BamHI-A rightward frame 1 (BARF1) is consistently detected in nasopharyngeal carcinomas (NPC) and EBV-associated gastric carcinomas (EBVaGCs) but is practically undetectable in B-cells and lymphomas. Although BARF1 is an early lytic gene, it is expressed during epithelial EBV latency, mainly as a secreted protein (sBARF1). The capacity of sBARF1 to disrupt both innate and adaptive host antiviral immune responses contributes to the immune escape of infected cells. Additionally, BARF1 increases cell proliferation, shows anti-apoptotic effects, and promotes an increased hTERT activity and tumor formation in nude mice cooperating with other host proteins such as c-Myc and H-ras. These facts allow for the consideration of BARF1 as a key protein for promoting EBV-associated epithelial tumors. In this review, we focus on structural and functional aspects of BARF1, such as mechanisms involved in epithelial carcinogenesis and its capacity to modulate the host immune response.

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Detection of lymphocytes productively infected with Epstein–Barr virus in non-neoplastic tonsils

Microbiology ◽

10.1099/0022-1317-81-5-1211 ◽

2000 ◽

Vol 81 (5) ◽

pp. 1211-1216 ◽

Cited By ~ 23

Author(s):

Tetsuya Ikeda ◽

Ryo Kobayashi ◽

Manabu Horiuchi ◽

Yoshifumi Nagata ◽

Makoto Hasegawa ◽

...

Keyword(s):

Epstein Barr Virus ◽

Immune Surveillance ◽

Lymphoid Tissues ◽

Healthy Individuals ◽

Barr Virus ◽

Multiple Copies ◽

The Face ◽

Infected Cells ◽

Epstein Barr

Epstein–Barr virus (EBV) persists for life in the infected host. Little is known about EBV reactivation and regulation of virus persistence in healthy individuals. We examined tonsils of chronic tonsillitis patients to detect EBV transcripts, EBV genomes and lytic proteins. LMP1 transcripts were observed in 11 of 15 specimens and BZLF1 transcripts were detected in six. Multiple copies of EBV genome equivalents per cell, and ZEBRA- and viral capsid antigen-positive cells were also detected in tonsillar lymphocytes. These results indicate that EBV productively infected cells may survive in the face of immune surveillance in the tonsils. Thus, EBV replication may occur in tonsillar lymphocytes, and tonsillar lymphoid tissues may play a role in the maintenance of EBV load in vivo.

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The EBNA1 Protein of Epstein-Barr Virus Functionally Interacts with Brd4

Journal of Virology ◽

10.1128/jvi.01680-08 ◽

2008 ◽

Vol 82 (24) ◽

pp. 12009-12019 ◽

Cited By ~ 68

Author(s):

Ammy Lin ◽

Shan Wang ◽

Tin Nguyen ◽

Kathy Shire ◽

Lori Frappier

Keyword(s):

Transcriptional Activation ◽

Epstein Barr Virus ◽

Mitotic Chromosome ◽

Human Cells ◽

Host Proteins ◽

Enhancer Element ◽

Barr Virus ◽

Chromosome Attachment ◽

Infected Cells ◽

Epstein Barr

ABSTRACT The EBNA1 protein of Epstein-Barr virus (EBV) is essential for EBV latent infection in ensuring the replication and stable segregation of the EBV genomes and in activating the transcription of other EBV latency genes. We have tested the ability of four host proteins (Brd2, Brd4, DEK, and MeCP2) implicated in the segregation of papillomavirus and Kaposi's sarcoma-associated herpesvirus to support EBNA1-mediated segregation of EBV-based plasmids in Saccharomyces cerevisiae. We found that Brd4 enabled EBNA1-mediated segregation while Brd2 and MeCP2 had a general stimulatory effect on plasmid maintenance. EBNA1 interacted with Brd4 in both yeast and human cells through N-terminal sequences previously shown to mediate transcriptional activation but not segregation. In keeping with this interaction site, silencing of Brd4 in human cells decreased transcriptional activation by EBNA1 but not the mitotic chromosome attachment of EBNA1 that is required for segregation. In addition, Brd4 was found to be preferentially localized to the FR enhancer element regulated by EBNA1, over other EBV sequences, in latently EBV-infected cells. The results indicate that EBNA1 can functionally interact with Brd4 in native and heterologous systems and that this interaction facilitates transcriptional activation by EBNA1 from the FR element.

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Epstein–Barr Virus—Associated Malignancies and Immune Escape: The Role of the Tumor Microenvironment and Tumor Cell Evasion Strategies

Cancers ◽

10.3390/cancers13205189 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5189

Author(s):

Marcus Bauer ◽

Simon Jasinski-Bergner ◽

Ofer Mandelboim ◽

Claudia Wickenhauser ◽

Barbara Seliger

Keyword(s):

Tumor Microenvironment ◽

Epstein Barr Virus ◽

Immune Cell ◽

Immune Escape ◽

Barr Virus ◽

Ebv Infection ◽

Infected Cells ◽

Epstein Barr ◽

Immune Cell Subpopulations

The detailed mechanisms of Epstein–Barr virus (EBV) infection in the initiation and progression of EBV-associated malignancies are not yet completely understood. During the last years, new insights into the mechanisms of malignant transformation of EBV-infected cells including somatic mutations and epigenetic modifications, their impact on the microenvironment and resulting unique immune signatures related to immune system functional status and immune escape strategies have been reported. In this context, there exists increasing evidence that EBV-infected tumor cells can influence the tumor microenvironment to their own benefit by establishing an immune-suppressive surrounding. The identified mechanisms include EBV gene integration and latent expression of EBV-infection-triggered cytokines by tumor and/or bystander cells, e.g., cancer-associated fibroblasts with effects on the composition and spatial distribution of the immune cell subpopulations next to the infected cells, stroma constituents and extracellular vesicles. This review summarizes (i) the typical stages of the viral life cycle and EBV-associated transformation, (ii) strategies to detect EBV genome and activity and to differentiate various latency types, (iii) the role of the tumor microenvironment in EBV-associated malignancies, (iv) the different immune escape mechanisms and (v) their clinical relevance. This gained information will enhance the development of therapies against EBV-mediated diseases to improve patient outcome.

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The role of Epstein–Barr virus-encoded latent membrane proteins in host immune escape

Future Virology ◽

10.2217/fvl-2020-0320 ◽

2021 ◽

Author(s):

Yuanyuan Jiang ◽

Yuan Ding ◽

Shuzhen Liu ◽

Bing Luo

Keyword(s):

Membrane Proteins ◽

Epstein Barr Virus ◽

Immune Escape ◽

Immune Surveillance ◽

Host Cells ◽

Barr Virus ◽

Type Iv ◽

Infection Pattern ◽

Epstein Barr

Epstein–Barr virus (EBV) is a type IV herpesvirus that widely infects the vast majority of adults, and establishes a latent infection pattern in host cells to escape the clearance of immune system. The virus is intimately associated with the occurrence and progression of lymphomas and epithelial cell cancers. EBV latent membrane proteins (LMPs) can assist its immune escape by downregulating host immune response. Besides EBV, LMPs have important effects on the functions of exosomes and autophagy, which also help EBV to escape immune surveillance. These escape mechanisms may provide conditions for further development of EBV-associated tumors. In this article, we discussed the potential functions of EBV-encoded LMPs in promoting immune escape.

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Studies of Epstein-Barr Virus Antigens Using Immunoperoxidase and Immunofluorescence Techniques

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010011533x ◽

1975 ◽

Vol 33 ◽

pp. 342-343

Author(s):

R. Stephens ◽

K. Traul ◽

D. Woolf ◽

P. Gaudreau

Keyword(s):

Electron Microscopy ◽

Nasopharyngeal Carcinoma ◽

Epstein Barr Virus ◽

Barr Virus ◽

If Technique ◽

Infected Cells ◽

Virus Antigens ◽

Epstein Barr ◽

Virus Capsid Antigen ◽

Antigen Reactivity

A number of antigens have been found associated with persistent EBV infections of lymphoblastoid cells. Identification and localization of these antigens were principally by immunofluorescence (IF) techniques using sera from patients with nasopharyngeal carcinoma (NPC), Burkitt lymphoma (BL), and infectious mononucleosis (IM). Our study was mainly with three of the EBV related antigens, a) virus capsid antigen (VCA), b) membrane antigen (MA), and c) early antigens (EA) using immunoperoxidase (IP) techniques with electron microscopy (EM) to elucidate the sites of reactivity with EBV and EBV infected cells.Prior to labeling with horseradish peroxidase (HRP), sera from NPC, IM, and BL cases were characterized for various reactivities by the indirect IF technique. Modifications of the direct IP procedure described by Shabo and the indirect IP procedure of Leduc were made to enhance penetration of the cells and preservation of antigen reactivity.

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Identification of Epstein–Barr virus-infected CD27+ memory B-cells in liver or stem cell transplant patients

Journal of General Virology ◽

10.1099/vir.0.033712-0 ◽

2011 ◽

Vol 92 (11) ◽

pp. 2590-2595 ◽

Cited By ~ 3

Author(s):

Yoshinori Ito ◽

Shinji Kawabe ◽

Seiji Kojima ◽

Fumihiko Nakamura ◽

Yukihiro Nishiyama ◽

...

Keyword(s):

Liver Transplantation ◽

Stem Cell ◽

B Cells ◽

Epstein Barr Virus ◽

Peripheral Blood Lymphocytes ◽

Haematopoietic Stem Cell ◽

Cell Transplant ◽

Barr Virus ◽

Infected Cells ◽

Epstein Barr

To analyse the phenotype of Epstein–Barr virus (EBV)-infected lymphocytes in EBV-associated infections, cells from eight haematopoietic stem cell/liver transplantation recipients with elevated EBV viral loads were examined by a novel quantitative assay designed to identify EBV-infected cells by using a flow cytometric detection of fluorescent in situ hybridization (FISH) assay. By this assay, 0.05–0.78 % of peripheral blood lymphocytes tested positive for EBV, and the EBV-infected cells were CD20+ B-cells in all eight patients. Of the CD20+ EBV-infected lymphocytes, 48–83 % of cells tested IgD positive and 49–100 % of cells tested CD27 positive. Additionally, the number of EBV-infected cells assayed by using FISH was significantly correlated with the EBV-DNA load, as determined by real-time PCR (r 2 = 0.88, P<0.0001). The FISH assay enabled us to characterize EBV-infected cells and perform a quantitative analysis in patients with EBV infection after stem cell/liver transplantation.

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Acyclovir Improves the Efficacy of Chemoradiation in Nasopharyngeal Cancer Containing the Epstein Barr Virus Genome

10.1101/2020.10.18.343236 ◽

2020 ◽

Author(s):

Aditya Thandoni ◽

Andrew Zloza ◽

Devora Schiff ◽

Malay Rao ◽

Kwok-wai Lo ◽

...

Keyword(s):

Epstein Barr Virus ◽

Treatment Options ◽

Immune Surveillance ◽

Nasopharyngeal Cancer ◽

Standard Of Care ◽

Virus Genome ◽

Barr Virus ◽

Standard Of Care Treatment ◽

Epstein Barr

AbstractNasopharyngeal carcinoma (NPC) is a malignancy endemic to East Asia and is caused by Epstein-Barr Virus (EBV)-mediated cancerous transformation of epithelial cells. The standard of care treatment for NPC involves radiation and chemotherapy. While treatment outcomes continue to improve, up to 50% of patients can be expected to recur by five years, and additional innovative treatment options are needed. We posit that a potential way to do this is by targeting the underlying cause of malignant transformation, namely EBV. One method by which EBV escapes immune surveillance is by undergoing latent phase replication, during which EBV expression of immunogenic proteins is reduced. However, chemoradiation is known to drive conversion of EBV from a latent to a lytic phase. This creates an opportunity for the targeting of EBV-infected cells utilizing anti-viral drugs. Indeed, we found that combining acyclovir with cisplatin and radiation significantly decreases the viability of the EBV-infected C666-1 cell line. Western blot quantification revealed a resultant increase of thymidine kinase (TK) and apoptosis-inducing mediators, cleaved PARP (cPARP) and phosphorylated ERK (pERK). These studies suggest that the addition of anti-viral drugs to frontline chemoradiation may improve outcomes in patients treated for EBV-related NPC and future in vivo and clinical studies are needed.

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Epstein–Barr virus induces a distinct form of DNA-bound STAT1 compared with that found in interferon-stimulated B lymphocytes

Journal of General Virology ◽

10.1099/vir.0.82741-0 ◽

2007 ◽

Vol 88 (7) ◽

pp. 1876-1886 ◽

Cited By ~ 13

Author(s):

James McLaren ◽

Martin Rowe ◽

Paul Brennan

Keyword(s):

Dna Binding ◽

Epstein Barr Virus ◽

Lymphoblastoid Cell Lines ◽

Distinct Form ◽

Post Translational Modifications ◽

Constitutive Activation ◽

Barr Virus ◽

Molecular Identity ◽

Infected Cells ◽

Epstein Barr

Since ‘constitutive activation’ of STAT1 was first described in Epstein–Barr virus (EBV)-immortalized lymphoblastoid cell lines (LCLs), there has been controversy regarding the molecular identity of the STAT1 DNA-binding complex found in these cells. The post-translational modifications of STAT1 in LCLs have been analysed and an LMP1-induced STAT1 DNA-binding complex, different from that generated by alpha interferon (IFN) stimulation and not involving tyrosine phosphorylation, is demonstrated. STAT1 is serine-phosphorylated downstream of PI3K and MEK in LCLs and this modification restricts IFN-stimulated STAT1–DNA binding. These data suggest that EBV induces a distinct form of DNA-bound STAT1 in virus-infected cells.

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