scholarly journals EPSTEIN-BARR VIRUS LMP1 ENHANCES LEVELS OF MICROVESICLE-ASSOCIATED PD-L1

2022 ◽  
Author(s):  
David G. Meckes ◽  
Monica Abou Harb ◽  
Li Sun
Keyword(s):  
Epstein Barr Virus ◽  
Cytotoxic T Cells ◽  
The Body ◽  
Carcinoma Cells ◽  
Barr Virus ◽  
Infected Cells ◽  
Delivery Vehicles ◽  
Epstein Barr ◽  
Immunosuppressive Microenvironment ◽  
Cell Death Protein

Extracellular vesicles (EVs) circulate throughout the body and carry cargo that can be conferred to proximal or distant cells, making them major delivery vehicles for cellular communication. Epstein-Barr virus (EBV) infected cells release EVs that contain viral proteins such as the major viral oncogene, latent membrane protein 1 (LMP1). LMP1 has been shown to regulate the cellular gene expression of programmed cell death protein 1 ligand (PD-L1). PD-L1, a protein that suppresses the immune system by binding to PD-1, (a receptor found on cytotoxic T cells). PD-L1 has been recently found to be packaged into small EVs contributing to immune evasion of lung cancer cells. Recent studies establish that MVs are shed in very large amounts by tumor cells, and that elevated levels of MVs correlate to disease metastasis and cancers being more aggressive. Here, we demonstrate PD-L1 enrichment in MVs released from nasopharyngeal carcinoma cells and an important function of EBV LMP1 in regulating PD-L1 levels in MVs. These PD-L1+ MVs containing LMP1 likely contribute to the immunosuppressive microenvironment found in EBV-associated cancers.

scholarly journals Autorepression of Epstein-Barr Virus Nuclear Antigen 1 Expression by Inhibition of Pre-mRNA Processing

2007 ◽  
Vol 82 (4) ◽  
pp. 1679-1687 ◽  
Author(s):  
Mikio Yoshioka ◽  
Michelle M. Crum ◽  
Jeffery T. Sample
Keyword(s):  
Cell Lines ◽  
Epstein Barr Virus ◽  
Rna Binding ◽  
Cytotoxic T Cells ◽  
Nuclear Antigen ◽  
Genome Maintenance ◽  
Barr Virus ◽  
Latently Infected ◽  
Infected Cells ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) latent infection, and its associated oncogenic potential, is dependent on genome maintenance functions of EBV nuclear antigen 1 (EBNA-1), one of six EBNAs expressed from a common promoter (Wp and then Cp) upon infection of naive B cells. Subsequent host-mediated silencing, however, necessitates the expression of EBNA-1 from the EBNA-1-specific promoter Qp to ensure against genome loss during cell division, including EBV-associated malignancy. Here we addressed the mechanism by which EBNA-1 represses Qp through binding downstream of the transcription start site and the role of this autoregulatory function in EBV latency. Our results revealed that EBNA-1 does not inhibit transcription from Qp, as previously predicted, but acts post- or cotranscriptionally to block the processing of primary transcripts. This does not, however, require the RGG motifs responsible for strong but nonspecific RNA binding by EBNA-1. Within isogenic B-cell lines using either Cp/Wp or Qp, EBNA-1 occupancy of Qp is equivalent, suggesting that autoregulation occurs, albeit to different degrees, during full and restricted EBV latency programs. Finally, in cell lines using Cp or Wp for EBNA expression, unprocessed transcripts from Qp are detectable in the absence of corresponding mRNAs, providing further evidence that this novel mechanism of EBNA-1 action functions during latency. This posttranscriptional mechanism of regulation would provide an efficient means to monitor and regulate EBNA-1 expression from Qp, ensuring levels adequate for genome maintenance but, perhaps more importantly, below an immunogenic threshold above which latently infected cells may be at risk for elimination by EBNA-1-specific cytotoxic T cells.

scholarly journals Epstein-Barr Virus Induces Expression of the LPAM-1 Integrin in B CellsIn VitroandIn Vivo

2018 ◽  
Vol 93 (5) ◽  
Author(s):  
Susanne Delecluse ◽  
Ming-Han Tsai ◽  
Anatoliy Shumilov ◽  
Maja Bencun ◽  
Sebastian Arrow ◽  
...  
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Digestive System ◽  
The Body ◽  
Barr Virus ◽  
Ebv Infection ◽  
Infected Cells ◽  
Epstein Barr

ABSTRACTEpstein-Barr virus (EBV) infects the oropharynx but, surprisingly, frequently induces B cell proliferation in the gut of immunosuppressed individuals. We found that EBV infectionin vitroinduces the expression of the LPAM-1 integrin on tonsillar B cells and increases it on peripheral blood cells. Similarly, LPAM-1 was induced in the tonsils of patients undergoing primary infectious mononucleosis. EBV-induced LPAM-1 bound to the MAdCAM-1 addressin, which allows B cell homing to the gastrointestinal mucosa-associated lymphoid tissue (GALT). Thus, we hypothesized that EBV-induced LPAM-1 could induce relocation of infected B cells from the tonsil to the GALT.In situhybridization with an EBER-specific probe revealed the frequent presence of EBV-infected cells in the pericolic lymph nodes of healthy individuals. Relocation of infected B cells into the GALT would expand the EBV reservoir, possibly protecting it from T cells primed in the oropharynx, and explain why EBV induces lymphoid tumors in the gut.IMPORTANCEEBV causes tumors in multiple organs, particularly in the oro- and nasopharyngeal area but also in the digestive system. This virus enters the body in the oropharynx and establishes a chronic infection in this area. The observation that the virus causes tumors in the digestive system implies that the infected cells can move to this organ. We found that EBV infection induces the expression of integrin beta 7 (ITGB7), an integrin that associates with integrin alpha 4 to form the LPAM-1 dimer. LPAM-1 is key for homing of B cells to the gastrointestinal tract, suggesting that induction of this molecule is the mechanism through which EBV-infected cells enter this organ. In favor of this hypothesis, we could also detect EBV-infected cells in the lymph nodes adjacent to the colon and in the appendix.

Downregulation of TAP1 in B Lymphocytes by Cellular and Epstein-Barr Virus–Encoded Interleukin-10

Blood ◽  
1997 ◽  
Vol 90 (6) ◽  
pp. 2390-2397 ◽  
Author(s):  
Reinhard Zeidler ◽  
Günther Eissner ◽  
Petra Meissner ◽  
Stephan Uebel ◽  
Robert Tampé ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
B Lymphocytes ◽  
Epstein Barr Virus ◽  
Cytotoxic T Cells ◽  
Interleukin 10 ◽  
Peptide Transporter ◽  
Mhc I ◽  
Barr Virus ◽  
Infected Cells ◽  
Epstein Barr

Abstract Virally infected cells degrade intracellular viral proteins proteolytically and present the resulting peptides in association with major histocompatibility complex (MHC) class I molecules to CD8+ cytotoxic T lymphocytes (CTLs). These cells are normally prone to CTL-mediated elimination. However, several viruses have evolved strategies to avoid detection by the immune system that interfere with the pathway of antigen presentation. Epstein-Barr virus (EBV) expresses a predominantly late protein, the BCRF1 gene product vIL-10, that is similar in sequence to the human interleukin-10 (hIL-10). We show here that vIL-10 affects the expression of one of the two transporter proteins (TAPs) associated with antigen presentation. Similarly, hIL-10 showed the same activity. Expression of the LMP2 and TAP1 genes but not expression of TAP2 or LMP7 is efficiently downregulated, indicating a specific IL-10 effect on the two divergently transcribed TAP1 and LMP2 genes. Downregulation of TAP1 by IL-10 hampers the transport of peptide antigens into the endoplasmatic reticulum, as shown in the TAP-specific peptide transporter assay, their loading onto empty MHC I molecules, and the subsequent translocation to the cell surface. As a consequence, IL-10 causes a general reduction of surface MHC I molecules on B lymphocytes that might also affect the recognition of EBV-infected cells by cytotoxic T cells.

scholarly journals Length of Epstein-Barr Virus Termini as a Determinant of Epithelial Cell Clonal Emergence

2003 ◽  
Vol 77 (15) ◽  
pp. 8555-8561 ◽  
Author(s):  
Cary A. Moody ◽  
Rona S. Scott ◽  
Tao Su ◽  
John W. Sixbey
Keyword(s):  
Epithelial Cell ◽  
Epstein Barr Virus ◽  
Cell Transformation ◽  
Carcinoma Cells ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Cell Clones ◽  
Infected Cells ◽  
Epstein Barr

ABSTRACT Reiterated terminal sequences of Epstein-Barr virus (EBV) DNA are numerically heterogeneous among infectious virions, providing a viral measure of clonality in infected cells. After in vitro infection, carcinoma cells bearing EBV episomes with fewer terminal repeats (TRs) proliferated faster. In single-cell clones, TR number varied inversely to the quantity of latent membrane protein 2A (LMP2A) transcripts whose unspliced precursors cross joined TRs. Thus, EBV clonality may reflect selection for a TR number that optimizes LMP2A-enhanced tumor progression, with infection occurring after epithelial cell transformation.

scholarly journals Downregulation of TAP1 in B Lymphocytes by Cellular and Epstein-Barr Virus–Encoded Interleukin-10

Blood ◽  
1997 ◽  
Vol 90 (6) ◽  
pp. 2390-2397 ◽  
Author(s):  
Reinhard Zeidler ◽  
Günther Eissner ◽  
Petra Meissner ◽  
Stephan Uebel ◽  
Robert Tampé ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
B Lymphocytes ◽  
Epstein Barr Virus ◽  
Cytotoxic T Cells ◽  
Interleukin 10 ◽  
Peptide Transporter ◽  
Mhc I ◽  
Barr Virus ◽  
Infected Cells ◽  
Epstein Barr

Virally infected cells degrade intracellular viral proteins proteolytically and present the resulting peptides in association with major histocompatibility complex (MHC) class I molecules to CD8+ cytotoxic T lymphocytes (CTLs). These cells are normally prone to CTL-mediated elimination. However, several viruses have evolved strategies to avoid detection by the immune system that interfere with the pathway of antigen presentation. Epstein-Barr virus (EBV) expresses a predominantly late protein, the BCRF1 gene product vIL-10, that is similar in sequence to the human interleukin-10 (hIL-10). We show here that vIL-10 affects the expression of one of the two transporter proteins (TAPs) associated with antigen presentation. Similarly, hIL-10 showed the same activity. Expression of the LMP2 and TAP1 genes but not expression of TAP2 or LMP7 is efficiently downregulated, indicating a specific IL-10 effect on the two divergently transcribed TAP1 and LMP2 genes. Downregulation of TAP1 by IL-10 hampers the transport of peptide antigens into the endoplasmatic reticulum, as shown in the TAP-specific peptide transporter assay, their loading onto empty MHC I molecules, and the subsequent translocation to the cell surface. As a consequence, IL-10 causes a general reduction of surface MHC I molecules on B lymphocytes that might also affect the recognition of EBV-infected cells by cytotoxic T cells.

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 Epstein-Barr virus-encoded LMP1 regulated Pim1 kinase expression promotes nasopharyngeal carcinoma cells proliferation

2019 ◽  
Vol Volume 12 ◽  
pp. 1137-1146 ◽  
Author(s):  
Ran-ran Ding ◽  
Jian-ling Yuan ◽  
Ya-nan Jia ◽  
Xiao-min Liao ◽  
Si-si Wang ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Epstein Barr Virus ◽  
Carcinoma Cells ◽  
Barr Virus ◽  
Pim1 Kinase ◽  
Epstein Barr ◽  
Kinase Expression

scholarly journals Selective Induction of Th2-Attracting Chemokines CCL17 and CCL22 in Human B Cells by Latent Membrane Protein 1 of Epstein-Barr Virus

2004 ◽  
Vol 78 (4) ◽  
pp. 1665-1674 ◽  
Author(s):  
Takashi Nakayama ◽  
Kunio Hieshima ◽  
Daisuke Nagakubo ◽  
Emiko Sato ◽  
Masahiro Nakayama ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
Epstein Barr Virus ◽  
Cytotoxic T Cells ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

ABSTRACT Chemokines are likely to play important roles in the pathophysiology of diseases associated with Epstein-Barr virus (EBV). Here, we have analyzed the repertoire of chemokines expressed by EBV-infected B cells. EBV infection of B cells induced expression of TARC/CCL17 and MDC/CCL22, which are known to attract Th2 cells and regulatory T cells via CCR4, and also upregulated constitutive expression of MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/CCL5, which are known to attract Th1 cells and cytotoxic T cells via CCR5. Accordingly, EBV-immortalized B cells secreted these chemokines, especially CCL3, CCL4, and CCL22, in large quantities. EBV infection or stable expression of LMP1 also induced CCL17 and CCL22 in a B-cell line, BJAB. The inhibitors of the TRAF/NF-κB pathway (BAY11-7082) and the p38/ATF2 pathway (SB202190) selectively suppressed the expression of CCL17 and CCL22 in EBV-immortalized B cells and BJAB-LMP1. Consistently, transient-transfection assays using CCL22 promoter-reporter constructs demonstrated that two NF-κB sites and a single AP-1 site were involved in the activation of the CCL22 promoter by LMP1. Finally, serum CCL22 levels were significantly elevated in infectious mononucleosis. Collectively, LMP1 induces CCL17 and CCL22 in EBV-infected B cells via activation of NF-κB and probably ATF2. Production of CCL17 and CCL22, which attract Th2 and regulatory T cells, may help EBV-infected B cells evade immune surveillance by Th1 cells. However, the concomitant production of CCL3, CCL4, and CCL5 by EBV-infected B cells may eventually attract Th1 cells and cytotoxic T cells, leading to elimination of EBV-infected B cells at latency III and to selection of those with limited expression of latent genes.

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