scholarly journals The Epstein-Barr Virus G-Protein-Coupled Receptor Contributes to Immune Evasion by Targeting MHC Class I Molecules for Degradation

2009 ◽  
Vol 5 (1) ◽  
pp. e1000255 ◽  
Author(s):  
Jianmin Zuo ◽  
Andrew Currin ◽  
Bryan D. Griffin ◽  
Claire Shannon-Lowe ◽  
Wendy A. Thomas ◽  
...  
Keyword(s):  
G Protein ◽  
Mhc Class I ◽  
Immune Evasion ◽  
Epstein Barr Virus ◽  
Class I ◽  
G Protein Coupled Receptor ◽  
Barr Virus ◽  
Epstein Barr ◽  
G Protein Coupled ◽  
Mhc Class I Molecules

scholarly journals Distinct Roles of Extracellular Domains in the Epstein-Barr Virus-Encoded BILF1 Receptor for Signaling and Major Histocompatibility Complex Class I Downregulation

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Suzan Fares ◽  
Katja Spiess ◽  
Emma T. B. Olesen ◽  
Jianmin Zuo ◽  
Sarah Jackson ◽  
...  
Keyword(s):  
G Protein ◽  
Mhc Class I ◽  
Epstein Barr Virus ◽  
Class I ◽  
Cysteine Residues ◽  
Conserved Residues ◽  
Barr Virus ◽  
Extracellular Domains ◽  
Epstein Barr ◽  
G Protein Coupled

ABSTRACTThe Epstein-Barr virus (EBV) BILF1 gene encodes a constitutively active G protein-coupled receptor (GPCR) that downregulates major histocompatibility complex (MHC) class I and induces signaling-dependent tumorigenesis. Different BILF1 homologs display highly conserved extracellular loops (ECLs) including the conserved cysteine residues involved in disulfide bridges present in class A GPCRs (GPCR bridge between transmembrane helix 3 [TM-3] and ECL-2) and in chemokine receptors (CKR bridge between the N terminus and ECL-3). In order to investigate the roles of the conserved residues in the receptor functions, 25 mutations were created in the extracellular domains. Luciferase reporter assays and flow cytometry were used to investigate the G protein signaling and MHC class I downregulation in HEK293 cells. We find that the cysteine residues involved in the GPCR bridge are important for both signaling and MHC class I downregulation, whereas the cysteine residues in the N terminus and ECL-3 are dispensable for signaling but important for MHC class I downregulation. Multiple conserved residues in the extracellular regions are important for the receptor-induced MHC class I downregulation, but not for signaling, indicating distinct structural requirements for these two functions. In an engineered receptor containing a binding site for Zn+2ions in a complex with an aromatic chelator (phenanthroline or bipyridine), a ligand-driven inhibition of both the receptor signaling and MHC class I downregulation was observed. Taken together, this suggests that distinct regions in EBV-BILF1 can be pharmacologically targeted to inhibit the signaling-mediated tumorigenesis and interfere with the MHC class I downregulation.IMPORTANCEG protein-coupled receptors constitute the largest family of membrane proteins. As targets of >30% of the FDA-approved drugs, they are valuable for drug discovery. The receptor is composed of seven membrane-spanning helices and intracellular and extracellular domains. BILF1 is a receptor encoded by Epstein-Barr virus (EBV), which evades the host immune system by various strategies. BILF1 facilitates the virus immune evasion by downregulating MHC class I and is capable of inducing signaling-mediated tumorigenesis. BILF1 homologs from primate viruses show highly conserved extracellular domains. Here, we show that conserved residues in the extracellular domains of EBV-BILF1 are important for downregulating MHC class I and that the receptor signaling and immune evasion can be inhibited by drug-like small molecules. This suggests that BILF1 could be a target to inhibit the signaling-mediated tumorigenesis and interfere with the MHC class I downregulation, thereby facilitating virus recognition by the immune system.

scholarly journals Analysis of Major Histocompatibility Complex Class I, TAP Expression, and LMP2 Epitope Sequence in Epstein-Barr Virus–Positive Hodgkin's Disease

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2477-2483 ◽  
Author(s):  
Paul G. Murray ◽  
Christothea M. Constandinou ◽  
John Crocker ◽  
Lawrence S. Young ◽  
Richard F. Ambinder
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
Epstein Barr Virus ◽  
Class I ◽  
Major Histocompatibility ◽  
Barr Virus ◽  
Histocompatibility Complex ◽  
Epstein Barr ◽  
Hla A2.1 ◽  
Mhc Class I Molecules

Abstract The Epstein-Barr virus (EBV)-encoded latent membrane proteins, LMP1 and LMP2, are consistently expressed by the malignant Hodgkin/Reed-Sternberg (HRS) cells of EBV-associated Hodgkin's disease (HD). Cytotoxic T lymphocyte (CTL) responses to both of these proteins have been shown in the blood of EBV-seropositive individuals, yet in HD the apparent failure of the CTL response to eliminate HRS cells expressing LMP1 and LMP2 in vivo has given rise to the suggestion that HD may be characterized by the presence of defects in antigen processing/presentation or in CTL function. This study has used immunohistochemistry to show high-level expression of major histocompatibility complex (MHC) class I molecules by the HRS cells of EBV-associated HD and either low level or absence of expression of MHC class I molecules on HRS cells of EBV-negative tumors. In addition, HRS cells expressed high levels of transporter-associated proteins (TAP-1, -2), irrespective of the presence of latent EBV infection. These results suggest that global downregulation of MHC class I molecules does not account for the apparent ability of EBV-infected HRS cells to evade CTL responses, but may be important in the understanding of EBV-negative disease.We have also sequenced an epitope in LMP2A (CLGGLLTMV) that is restricted through HLA A2.1, a relatively common allele in Caucasian populations, and showed that this epitope is wild type in a small group of EBV-associated HLA A2.1-positive HD tumors. This result may be relevant to proposed immunotherapeutic approaches for EBV-positive HD patients that target CTL epitopes.

scholarly journals The Switch from Latent to Productive Infection in Epstein-Barr Virus-Infected B Cells Is Associated with Sensitization to NK Cell Killing

2006 ◽  
Vol 81 (2) ◽  
pp. 474-482 ◽  
Author(s):  
Isabel Y. Pappworth ◽  
Eddie C. Wang ◽  
Martin Rowe
Keyword(s):  
B Cells ◽  
Nk Cells ◽  
Mhc Class I ◽  
Epstein Barr Virus ◽  
Nk Cell ◽  
Class I ◽  
Inhibitory Receptors ◽  
Barr Virus ◽  
Epstein Barr ◽  
Mhc Class I Molecules

ABSTRACT Following activation of Epstein-Barr virus (EBV)-infected B cells from latent to productive (lytic) infection, there is a concomitant reduction in the level of cell surface major histocompatibility complex (MHC) class I molecules and an impaired antigen-presenting function that may facilitate evasion from EBV-specific CD8+ cytotoxic T cells. In some other herpesviruses studied, most notably human cytomegalovirus (HCMV), evasion of virus-specific CD8+ effector responses via downregulation of surface MHC class I molecules is supplemented with specific mechanisms for evading NK cells. We now report that EBV differs from HCMV in this respect. While latently infected EBV-positive B cells were resistant to lysis by two NK lines and by primary polyclonal NK cells from peripheral blood, these effectors efficiently killed cells activated into the lytic cycle. Susceptibility to NK lysis coincided not only with downregulation of HLA-A, -B, and -C molecules that bind to the KIR family of inhibitory receptors on NK cells but also with downregulation of HLA-E molecules binding the CD94/NKG2A inhibitory receptors. Conversely, ULBP-1 and CD112, ligands for the NK cell-activating receptors NKG2D and DNAM-1, respectively, were elevated. Susceptibility of the virus-producing target cells to NK cell lysis was partially reversed by blocking ULBP-1 or CD112 with specific antibodies. These results highlight a fundamental difference between EBV and HCMV with regards to evasion of innate immunity.

scholarly journals Cell transformation mediated by the Epstein–Barr virus G protein-coupled receptor BILF1 is dependent on constitutive signaling

Oncogene ◽  
2010 ◽  
Vol 29 (31) ◽  
pp. 4388-4398 ◽  
Author(s):  
R Lyngaa ◽  
K Nørregaard ◽  
M Kristensen ◽  
V Kubale ◽  
M M Rosenkilde ◽  
...  
Keyword(s):  
G Protein ◽  
Epstein Barr Virus ◽  
Cell Transformation ◽  
G Protein Coupled Receptor ◽  
Barr Virus ◽  
Epstein Barr ◽  
G Protein Coupled

scholarly journals Biased agonism and allosteric modulation of G protein-coupled receptor 183 - a 7TM receptor also known as Epstein-Barr virus-induced gene 2

2017 ◽  
Vol 174 (13) ◽  
pp. 2031-2042 ◽  
Author(s):  
Viktorija Daugvilaite ◽  
Christian Medom Madsen ◽  
Michael Lückmann ◽  
Clara Castello Echeverria ◽  
Andreas Walter Sailer ◽  
...  
Keyword(s):  
G Protein ◽  
Epstein Barr Virus ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptor ◽  
Biased Agonism ◽  
Barr Virus ◽  
Epstein Barr ◽  
G Protein Coupled

scholarly journals Identification and Functional Comparison of Seven-Transmembrane G-Protein-Coupled BILF1 Receptors in Recently Discovered Nonhuman Primate Lymphocryptoviruses

2014 ◽  
Vol 89 (4) ◽  
pp. 2253-2267 ◽  
Author(s):  
Katja Spiess ◽  
Suzan Fares ◽  
Alexander H. Sparre-Ulrich ◽  
Ellen Hilgenberg ◽  
Michael A. Jarvis ◽  
...  
Keyword(s):  
Phylogenetic Analysis ◽  
G Protein ◽  
Immune Evasion ◽  
Epstein Barr Virus ◽  
New World ◽  
Surface Expression ◽  
Barr Virus ◽  
Epstein Barr ◽  
G Protein Coupled ◽  
Insight Into

ABSTRACTCoevolution of herpesviruses with their respective host has resulted in a delicate balance between virus-encoded immune evasion mechanisms and host antiviral immunity. BILF1 encoded by human Epstein-Barr virus (EBV) is a 7-transmembrane (7TM) G-protein-coupled receptor (GPCR) with multiple immunomodulatory functions, including attenuation of PKR phosphorylation, activation of G-protein signaling, and downregulation of major histocompatibility complex (MHC) class I surface expression. In this study, we explored the evolutionary and functional relationships between BILF1 receptor family members from EBV and 12 previously uncharacterized nonhuman primate (NHP) lymphocryptoviruses (LCVs). Phylogenetic analysis defined 3 BILF1 clades, corresponding to LCVs of New World monkeys (clade A) or Old World monkeys and great apes (clades B and C). Common functional properties were suggested by a high degree of sequence conservation in functionally important regions of the BILF1 molecules. A subset of BILF1 receptors from EBV and LCVs from NHPs (chimpanzee, orangutan, marmoset, and siamang) were selected for multifunctional analysis. All receptors exhibited constitutive signaling activity via G protein Gαi and induced activation of the NF-κB transcription factor. In contrast, only 3 of 5 were able to activate NFAT (nuclear factor of activated T cells); chimpanzee and orangutan BILF1 molecules were unable to activate NFAT. Similarly, although all receptors were internalized, BILF1 from the chimpanzee and orangutan displayed an altered cellular localization pattern with predominant cell surface expression. This study shows how biochemical characterization of functionally important orthologous viral proteins can be used to complement phylogenetic analysis to provide further insight into diverse microbial evolutionary relationships and immune evasion function.IMPORTANCEEpstein-Barr virus (EBV), known as an oncovirus, is the only human herpesvirus in the genusLymphocryptovirus(LCV). EBV uses multiple strategies to hijack infected host cells, establish persistent infection in B cells, and evade antiviral immune responses. As part of EBV's immune evasion strategy, the virus encodes a multifunctional 7-transmembrane (7TM) G-protein-coupled receptor (GPCR), EBV BILF1. In addition to multiple immune evasion-associated functions, EBV BILF1 has transforming properties, which are linked to its high constitutive activity. We identified BILF1 receptor orthologues in 12 previously uncharacterized LCVs from nonhuman primates (NHPs) of Old and New World origin. As 7TM receptors are excellent drug targets, our unique insight into the molecular mechanism of action of the BILF1 family and into the evolution of primate LCVs may enable validation of EBV BILF1 as a drug target for EBV-mediated diseases, as well as facilitating the design of drugs targeting EBV BILF1.

scholarly journals Analysis of Major Histocompatibility Complex Class I, TAP Expression, and LMP2 Epitope Sequence in Epstein-Barr Virus–Positive Hodgkin's Disease

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2477-2483 ◽  
Author(s):  
Paul G. Murray ◽  
Christothea M. Constandinou ◽  
John Crocker ◽  
Lawrence S. Young ◽  
Richard F. Ambinder
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
Epstein Barr Virus ◽  
Class I ◽  
Major Histocompatibility ◽  
Barr Virus ◽  
Histocompatibility Complex ◽  
Epstein Barr ◽  
Hla A2.1 ◽  
Mhc Class I Molecules

The Epstein-Barr virus (EBV)-encoded latent membrane proteins, LMP1 and LMP2, are consistently expressed by the malignant Hodgkin/Reed-Sternberg (HRS) cells of EBV-associated Hodgkin's disease (HD). Cytotoxic T lymphocyte (CTL) responses to both of these proteins have been shown in the blood of EBV-seropositive individuals, yet in HD the apparent failure of the CTL response to eliminate HRS cells expressing LMP1 and LMP2 in vivo has given rise to the suggestion that HD may be characterized by the presence of defects in antigen processing/presentation or in CTL function. This study has used immunohistochemistry to show high-level expression of major histocompatibility complex (MHC) class I molecules by the HRS cells of EBV-associated HD and either low level or absence of expression of MHC class I molecules on HRS cells of EBV-negative tumors. In addition, HRS cells expressed high levels of transporter-associated proteins (TAP-1, -2), irrespective of the presence of latent EBV infection. These results suggest that global downregulation of MHC class I molecules does not account for the apparent ability of EBV-infected HRS cells to evade CTL responses, but may be important in the understanding of EBV-negative disease.We have also sequenced an epitope in LMP2A (CLGGLLTMV) that is restricted through HLA A2.1, a relatively common allele in Caucasian populations, and showed that this epitope is wild type in a small group of EBV-associated HLA A2.1-positive HD tumors. This result may be relevant to proposed immunotherapeutic approaches for EBV-positive HD patients that target CTL epitopes.

scholarly journals The Epstein-Barr Virus BILF1 Gene Encodes a G Protein-Coupled Receptor That Inhibits Phosphorylation of RNA-Dependent Protein Kinase

2005 ◽  
Vol 79 (1) ◽  
pp. 441-449 ◽  
Author(s):  
Patrick S. Beisser ◽  
Dennis Verzijl ◽  
Yvonne K. Gruijthuijsen ◽  
Erik Beuken ◽  
Martine J. Smit ◽  
...  
Keyword(s):  
Protein Kinase ◽  
G Protein ◽  
Epstein Barr Virus ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
G Protein Coupled Receptor ◽  
Lymphoma Cells ◽  
Barr Virus ◽  
Epstein Barr ◽  
G Protein Coupled

ABSTRACT Epstein-Barr virus (EBV) infection is associated with many lymphoproliferative diseases, such as infectious mononucleosis and Burkitt's lymphoma. Consequently, EBV is one of the most extensively studied herpesviruses. Surprisingly, a putative G protein-coupled receptor (GPCR) gene of EBV, BILF1, has hitherto escaped attention, yet BILF1-like genes are conserved among all known lymphocryptovirus species, suggesting that they play a pivotal role in viral infection. To determine the function of EBV BILF1, the activity of this gene and its products was studied. BILF1-specific mRNA was detected in various EBV-positive cell types and found to be expressed predominantly during the immediate early and early phases of infection in vitro. Interestingly, in COS-7 cells transfected with BILF1 expression constructs, a decrease in forskolin-induced CRE-mediated transcription was measured, as well as an increase in NF-κB-mediated transcription. In contrast, CRE-mediated transcription was increased in EBV-positive Burkitt's lymphoma cells as well as EBV-positive lymphoblastoid B cells transfected with BILF1, whereas NF-κB-mediated transcription levels remained unaffected in these cells. All observed activities were sensitive to treatment with pertussis toxin, indicating that the BILF1-encoded protein mediates these activities by coupling to G proteins of the Gi/o class. Finally, reduced levels of phosphorylated RNA-dependent antiviral protein kinase were observed in COS-7 and Burkitt's lymphoma cells transfected with BILF1. Neither of the observed effects required a ligand to interact with the BILF1 gene product, suggesting that BILF1 encodes a constitutively active GPCR capable of modulating various intracellular signaling pathways.

Sign in / Sign up

Export Citation Format

Share Document