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

Biology ◽  
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.

scholarly journals Oncogenic Properties of the EBV ZEBRA Protein

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1479
Author(s):  
Diego Germini ◽  
Fatimata Bintou Sall ◽  
Anna Shmakova ◽  
Joëlle Wiels ◽  
Svetlana Dokudovskaya ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Immune Escape ◽  
Immune Surveillance ◽  
Host Proteins ◽  
Barr Virus ◽  
Infected Cells ◽  
Functional Features ◽  
Epstein Barr ◽  
Human Herpesviruses ◽  
Transcriptional Transactivator

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.

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

Cancers ◽  
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.

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

2008 ◽  
Vol 82 (24) ◽  
pp. 12009-12019 ◽  
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.

scholarly journals Role of ATM in the Formation of the Replication Compartment during Lytic Replication of Epstein-Barr Virus in Nasopharyngeal Epithelial Cells

2014 ◽  
Vol 89 (1) ◽  
pp. 652-668 ◽  
Author(s):  
Pok Man Hau ◽  
Wen Deng ◽  
Lin Jia ◽  
Jie Yang ◽  
Tatsuya Tsurumi ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Viral Replication ◽  
Epstein Barr Virus ◽  
Viral Dna ◽  
Barr Virus ◽  
Lytic Reactivation ◽  
Infected Cells ◽  
Epstein Barr ◽  
Replication Compartment

ABSTRACTEpstein-Barr virus (EBV), a type of oncogenic herpesvirus, is associated with human malignancies. Previous studies have shown that lytic reactivation of EBV in latently infected cells induces an ATM-dependent DNA damage response (DDR). The involvement of ATM activation has been implicated in inducing viral lytic gene transcription to promote lytic reactivation. Its contribution to the formation of a replication compartment during lytic reactivation of EBV remains poorly defined. In this study, the role of ATM in viral DNA replication was investigated in EBV-infected nasopharyngeal epithelial cells. We observed that induction of lytic infection of EBV triggers ATM activation and localization of DDR proteins at the viral replication compartments. Suppression of ATM activity using a small interfering RNA (siRNA) approach or a specific chemical inhibitor profoundly suppressed replication of EBV DNA and production of infectious virions in EBV-infected cells induced to undergo lytic reactivation. We further showed that phosphorylation of Sp1 at the serine-101 residue is essential in promoting the accretion of EBV replication proteins at the replication compartment, which is crucial for replication of viral DNA. Knockdown of Sp1 expression by siRNA effectively suppressed the replication of viral DNA and localization of EBV replication proteins to the replication compartments. Our study supports an important role of ATM activation in lytic reactivation of EBV in epithelial cells, and phosphorylation of Sp1 is an essential process downstream of ATM activation involved in the formation of viral replication compartments. Our study revealed an essential role of the ATM-dependent DDR pathway in lytic reactivation of EBV, suggesting a potential antiviral replication strategy using specific DDR inhibitors.IMPORTANCEEpstein-Barr virus (EBV) is closely associated with human malignancies, including undifferentiated nasopharyngeal carcinoma (NPC), which has a high prevalence in southern China. EBV can establish either latent or lytic infection depending on the cellular context of infected host cells. Recent studies have highlighted the importance of the DNA damage response (DDR), a surveillance mechanism that evolves to maintain genome integrity, in regulating lytic EBV replication. However, the underlying molecular events are largely undefined. ATM is consistently activated in EBV-infected epithelial cells when they are induced to undergo lytic reactivation. Suppression of ATM inhibits replication of viral DNA. Furthermore, we observed that phosphorylation of Sp1 at the serine-101 residue, a downstream event of ATM activation, plays an essential role in the formation of viral replication compartments for replication of virus DNA. Our study provides new insights into the mechanism through which EBV utilizes the host cell machinery to promote replication of viral DNA upon lytic reactivation.

scholarly journals Epstein-Barr virus and human diseases: recent advances in diagnosis.

1988 ◽  
Vol 1 (3) ◽  
pp. 300-312 ◽  
Author(s):  
M Okano ◽  
G M Thiele ◽  
J R Davis ◽  
H L Grierson ◽  
D T Purtilo
Keyword(s):  
Epstein Barr Virus ◽  
Recent Decade ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Human Diseases ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Infected Cells ◽  
Epstein Barr

Since the discovery of Epstein-Barr virus (EBV) from a cultured Burkitt's lymphoma cell line in 1964, the virus has been associated with Burkitt's lymphoma, nasopharyngeal carcinoma, and infectious mononucleosis. During the recent decade, EBV has been etiologically implicated in a broad spectrum of human diseases. The precise role of this virus in these diseases is not well understood, but clearly, defective immunosurveillance against the virus may permit an uncontrolled proliferation of EBV-infected cells. As a result, a growing number of cases of EBV-associated B-cell proliferative diseases or lymphoma have been noted in patients with primary and acquired immunodeficiencies. These lymphoproliferative diseases and others, such as chronic mononucleosis syndrome, are leading to new areas of investigation which are providing information regarding the pathogenetic mechanisms of EBV-induced diseases. The early accurate diagnosis of EBV infection can be achieved by performing EBV-specific serology, detecting for EBV-determined nuclear antigen in tissues, establishing spontaneous lymphoid cell lines, and using molecular hybridization techniques for demonstrating the presence of viral genome in affected lesions.

scholarly journals Inducible loss of NF-κB activity is associated with apoptosis and Bcl-2 down-regulation in Epstein-Barr virus-transformed B lymphocytes

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 2068-2075 ◽  
Author(s):  
Jean Feuillard ◽  
Marino Schuhmacher ◽  
Sylvie Kohanna ◽  
Marianne Asso–Bonnet ◽  
Frédérique Ledeur ◽  
...  
Keyword(s):  
B Lymphocytes ◽  
Epstein Barr Virus ◽  
Target Genes ◽  
Regulatory Sequences ◽  
Dependent Manner ◽  
Protein Levels ◽  
Barr Virus ◽  
Infected Cells ◽  
Epstein Barr

Abstract The Epstein–Barr virus (EBV)-encoded latent membrane protein-1 induces NF-κB activity by targeting IκBα. To understand the role of NF-κB activation in EBV-related oncogenesis, we have subcloned mutated IκBα32/36A cDNA into a pHEBo vector containing doxycycline regulatory sequences and stably transfected this construct into a lymphoblastoid cell line. Two tightly regulated clones were obtained in which IκBα32/36A was inducible in a doxycycline dose-dependent manner. Levels of inducible IκBα32/36A peaked at day 2. Inhibition of NF-κB activity was closely correlated with levels of inducible IκBα32/36A. Levels of 3 well-known NF-κB-dependent genes, CD54, p105, and endogenous IκBα, were decreased when IκBα32/36A was induced, and the growth of IκBα32/36A-induced EBV-infected cells was slightly reduced. Loss of NF-κB activity was associated with decreased Bcl-2 protein levels. Finally, the induction of apoptosis was strongly increased in IκBα32/36A-overexpressing cells. Together these results show that it is possible to control IκBα32/36A levels, ie, NF-κB activity, in EBV-infected B-lymphocytes using a doxycycline-inducible vector. Moreover, our results indicate that NF-κB can protect EBV-infected cells from apoptosis by Bcl-2. Finally, our results suggest that a cellular model with doxycycline-inducible IκBα32/36A may be useful in the identification of genuine NF-κB target genes in EBV-infected B cells.

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

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.

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

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.

scholarly journals Molecular Genetics in Epstein–Barr Virus-Associated Malignancies

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 593
Author(s):  
Srikanth Umakanthan ◽  
Maryann M Bukelo
Keyword(s):  
Epstein Barr Virus ◽  
Diagnostic Tools ◽  
Main Role ◽  
Genetic Changes ◽  
Barr Virus ◽  
Cancer Pathogenesis ◽  
Genomic Studies ◽  
Epstein Barr ◽  
Oncogenic Form

Global genomic studies have detected the role of genomic alterations in the pathogenesis of Epstein–Barr virus (EBV)-associated tumors. EBV oncoproteins cause a vital shift of EBV from an infectious virus to an oncogenic form during the latent and lytic phase within the lymphoid B cells and epithelial cells. This epigenetic alteration modulates the virus and host genomes and inactivates and disrupts numerous tumor suppressors and signaling pathways. Genomic profiling has played the main role in identifying EBV cancer pathogenesis and its related targeted therapies. This article reviews the role of genetic changes in EBV-associated lymphomas and carcinomas. This includes the prolific molecular genesis, key diagnostic tools, and target-specific drugs that have been in recent clinical use.

Sign in / Sign up

Export Citation Format

Share Document