scholarly journals Epstein-Barr Virus gp42 Is Posttranslationally Modified To Produce Soluble gp42 That Mediates HLA Class II Immune Evasion

2005 ◽  
Vol 79 (2) ◽  
pp. 841-852 ◽  
Author(s):  
Maaike E. Ressing ◽  
Daphne van Leeuwen ◽  
Frank A. W. Verreck ◽  
Sinéad Keating ◽  
Raquel Gomez ◽  
...  
Keyword(s):  
T Cell ◽  
Epstein Barr Virus ◽  
Human Leukocyte ◽  
Class Ii ◽  
Hla Class Ii ◽  
Lytic Cycle ◽  
Soluble Form ◽  
Barr Virus ◽  
Cell Immunity ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) resides as a persistent infection in human leukocyte antigen (HLA) class II+ B lymphocytes and is associated with a number of malignancies. The EBV lytic-phase protein gp42 serves at least two functions: gp42 acts as the coreceptor for viral entry into B cells and hampers T-cell recognition via HLA class II molecules through steric hindrance of T-cell receptor-class II-peptide interactions. Here, we show that gp42 associates with class II molecules at their various stages of maturation, including immature αβIi heterotrimers and mature αβ-peptide complexes. When analyzing the biosynthesis and maturation of gp42 in cells stably expressing the viral protein, we found that gp42 occurs in two forms: a full-length type II membrane protein and a truncated soluble form. Soluble gp42 is generated by proteolytic cleavage in the endoplasmic reticulum and is secreted. Soluble gp42 is sufficient to inhibit HLA class II-restricted antigen presentation to T cells. In an almost pure population of Burkitt's lymphoma cells in the EBV lytic cycle, both transmembrane and soluble forms of gp42 are detected. These results imply that soluble gp42 is generated during EBV lytic infection and could contribute to undetected virus production by mediating evasion from T-cell immunity.

scholarly journals CD4+ T-Cell Responses to Epstein-Barr Virus (EBV) Latent-Cycle Antigens and the Recognition of EBV-Transformed Lymphoblastoid Cell Lines

2005 ◽  
Vol 79 (8) ◽  
pp. 4896-4907 ◽  
Author(s):  
H. M. Long ◽  
T. A. Haigh ◽  
N. H. Gudgeon ◽  
A. M. Leen ◽  
C.-W. Tsang ◽  
...  
Keyword(s):  
T Cell ◽  
Epstein Barr Virus ◽  
T Cell Responses ◽  
Class Ii ◽  
Hla Class Ii ◽  
Target Cells ◽  
Barr Virus ◽  
Cell Responses ◽  
Latently Infected ◽  
Epstein Barr

ABSTRACT There is considerable interest in the potential of Epstein-Barr virus (EBV) latent antigen-specific CD4+ T cells to act as direct effectors controlling EBV-induced B lymphoproliferations. Such activity would require direct CD4+ T-cell recognition of latently infected cells through epitopes derived from endogenously expressed viral proteins and presented on the target cell surface in association with HLA class II molecules. It is therefore important to know how often these conditions are met. Here we provide CD4+ epitope maps for four EBV nuclear antigens, EBNA1, -2, -3A, and -3C, and establish CD4+ T-cell clones against 12 representative epitopes. For each epitope we identify the relevant HLA class II restricting allele and determine the efficiency with which epitope-specific effectors recognize the autologous EBV-transformed B-lymphoblastoid cell line (LCL). The level of recognition measured by gamma interferon release was consistent among clones to the same epitope but varied between epitopes, with values ranging from 0 to 35% of the maximum seen against the epitope peptide-loaded LCL. These epitope-specific differences, also apparent in short-term cytotoxicity and longer-term outgrowth assays on LCL targets, did not relate to the identity of the source antigen and could not be explained by the different functional avidities of the CD4+ clones; rather, they appeared to reflect different levels of epitope display at the LCL surface. Thus, while CD4+ T-cell responses are detectable against many epitopes in EBV latent proteins, only a minority of these responses are likely to have therapeutic potential as effectors directly recognizing latently infected target cells.

scholarly journals Epstein-Barr Virus Isolates Retain Their Capacity To Evade T Cell Immunity through BNLF2a despite Extensive Sequence Variation

2011 ◽  
Vol 86 (1) ◽  
pp. 572-577 ◽  
Author(s):  
D. Horst ◽  
S. R. Burrows ◽  
D. Gatherer ◽  
B. van Wilgenburg ◽  
M. J. Bell ◽  
...  
Keyword(s):  
T Cell ◽  
Epstein Barr Virus ◽  
Sequence Variation ◽  
T Cell Immunity ◽  
Extensive Sequence ◽  
Barr Virus ◽  
Cell Immunity ◽  
Epstein Barr ◽  
Virus Isolates

Reconstitution of the Epstein-Barr virus–specific cytotoxic T-lymphocyte response following T-cell–depleted myeloablative and nonmyeloablative allogeneic stem cell transplantation

Blood ◽  
2003 ◽  
Vol 102 (3) ◽  
pp. 839-842 ◽  
Author(s):  
Suparno Chakrabarti ◽  
Donald W. Milligan ◽  
Deenan Pillay ◽  
Stephen Mackinnon ◽  
Kathleen Holder ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Epstein Barr Virus ◽  
Specific Response ◽  
Virus Infections ◽  
Barr Virus ◽  
Cell Immunity ◽  
Epstein Barr

AbstractThe recovery of circulating antigen-specific T-cell immunity to Epstein-Barr virus (EBV) was determined in ELIspot assays following allogeneic myeloablative or nonmyeloablative stem cell transplantation (MST/NST). In 8 of 12 MST patients receiving an alemtuzumab-treated graft, the frequency of the EBV-specific reactivities was similar to or greater than that seen in the healthy controls. A response was detectable in 3 of 6 and 6 of 9 patients by 3 and 6 months, respectively, and in all patients by one year following MST. In contrast, only 1 of 9 (95% confidence interval [CI], 0-2.8) patients made a detectable EBV-specific response by 6 months following NST conditioned with fludarabine, melphalan, and alemtuzumab. Responses were detected in 7 of 10 patients by 1 year after NST. Parallel surveillance demonstrated that other virus infections occurred more frequently and earlier after transplantation in NST patients. The use of alemtuzumab in vivo in the nonmyeloablative conditioning might have resulted in the delay in EBV-specific T-cell recovery and increased virus infections.

scholarly journals CD8+ immunodominance among Epstein-Barr virus lytic cycle antigens directly reflects the efficiency of antigen presentation in lytically infected cells

2005 ◽  
Vol 201 (3) ◽  
pp. 349-360 ◽  
Author(s):  
Victoria A. Pudney ◽  
Alison M. Leese ◽  
Alan B. Rickinson ◽  
Andrew D. Hislop
Keyword(s):  
T Cell ◽  
Epstein Barr Virus ◽  
Cd8 T Cell ◽  
Lytic Replication ◽  
Lytic Cycle ◽  
E Proteins ◽  
Barr Virus ◽  
Infected Cells ◽  
Epstein Barr ◽  
L Proteins

Antigen immunodominance is an unexplained feature of CD8+ T cell responses to herpesviruses, which are agents whose lytic replication involves the sequential expression of immediate early (IE), early (E), and late (L) proteins. Here, we analyze the primary CD8 response to Epstein-Barr virus (EBV) infection for reactivity to 2 IE proteins, 11 representative E proteins, and 10 representative L proteins, across a range of HLA backgrounds. Responses were consistently skewed toward epitopes in IE and a subset of E proteins, with only occasional responses to novel epitopes in L proteins. CD8+ T cell clones to representative IE, E, and L epitopes were assayed against EBV-transformed lymphoblastoid cell lines (LCLs) containing lytically infected cells. This showed direct recognition of lytically infected cells by all three sets of effectors but at markedly different levels, in the order IE > E ≫ L, indicating that the efficiency of epitope presentation falls dramatically with progress of the lytic cycle. Thus, EBV lytic cycle antigens display a hierarchy of immunodominance that directly reflects the efficiency of their presentation in lytically infected cells; the CD8+ T cell response thereby focuses on targets whose recognition leads to maximal biologic effect.

A comparison of epstein-barr virus-specific T-cell immunity in malaria-endemic and -nonendemic regions of Papua New Guinea

1983 ◽  
Vol 31 (6) ◽  
pp. 727-732 ◽  
Author(s):  
D. J. Moss ◽  
S. R. Burrows ◽  
D. J. Castelino ◽  
R. G. Kane ◽  
J. H. Pope ◽  
...  
Keyword(s):  
T Cell ◽  
Papua New Guinea ◽  
Epstein Barr Virus ◽  
New Guinea ◽  
T Cell Immunity ◽  
Barr Virus ◽  
Cell Immunity ◽  
Epstein Barr

scholarly journals Epstein-Barr Virus Evades CD4+ T Cell Responses in Lytic Cycle through BZLF1-mediated Downregulation of CD74 and the Cooperation of vBcl-2

2011 ◽  
Vol 7 (12) ◽  
pp. e1002455 ◽  
Author(s):  
Jianmin Zuo ◽  
Wendy A. Thomas ◽  
Tracey A. Haigh ◽  
Leah Fitzsimmons ◽  
Heather M. Long ◽  
...  
Keyword(s):  
T Cell ◽  
Epstein Barr Virus ◽  
T Cell Responses ◽  
Lytic Cycle ◽  
Cd4 T Cell ◽  
Barr Virus ◽  
Cell Responses ◽  
Epstein Barr

scholarly journals Epstein?Barr virus T-cell immunity despite rituximab

2007 ◽  
Vol 136 (4) ◽  
pp. 628-632 ◽  
Author(s):  
Angela K. Nehring ◽  
Ujjwal Dua ◽  
Peter Mollee ◽  
Devinder Gill ◽  
Karen Grimmett ◽  
...  
Keyword(s):  
T Cell ◽  
Epstein Barr Virus ◽  
T Cell Immunity ◽  
Barr Virus ◽  
Cell Immunity ◽  
Epstein Barr

scholarly journals Cleavage and Secretion of Epstein-Barr Virus Glycoprotein 42 Promote Membrane Fusion with B Lymphocytes

2009 ◽  
Vol 83 (13) ◽  
pp. 6664-6672 ◽  
Author(s):  
Jessica Sorem ◽  
Theodore S. Jardetzky ◽  
Richard Longnecker
Keyword(s):  
Membrane Fusion ◽  
B Lymphocytes ◽  
Viral Entry ◽  
Epstein Barr Virus ◽  
Class Ii ◽  
Hla Class Ii ◽  
Full Length ◽  
Barr Virus ◽  
Infected Cells ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) membrane glycoprotein 42 (gp42) is required for viral entry into B lymphocytes through binding to human leukocyte antigen (HLA) class II on the B-cell surface. EBV gp42 plays multiple roles during infection, including acting as a coreceptor for viral entry into B cells, binding to EBV glycoprotein H (gH) and gL during the process of membrane fusion, and blocking T-cell recognition of HLA class II-peptide complexes through steric hindrance. EBV gp42 occurs in two forms in infected cells, a full-length membrane-bound form and a soluble form generated by proteolytic cleavage that is secreted from infected cells due to loss of the N-terminal transmembrane domain. Both the full-length and the secreted gp42 forms bind to gH/gL and HLA class II, and the functional significance of gp42 cleavage is currently unclear. We found that in a virus-free cell-cell fusion assay, enhanced secretion of gp42 promoted fusion with B lymphocytes, and mutation of the site of gp42 cleavage inhibited membrane fusion activity. The site of gp42 cleavage was found to be physically distinct from the residues of gp42 necessary for binding to gH/gL. These results suggest that cleavage and secretion of gp42 are necessary for the process of membrane fusion with B lymphocytes, providing the first indicated functional difference between full-length and cleaved, secreted gp42.

scholarly journals Sustained Clinical Improvement in a Subset of Patients With Progressive Multiple Sclerosis Treated With Epstein–Barr Virus-Specific T Cell Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Zara A. Ioannides ◽  
Peter A. Csurhes ◽  
Nanette L. Douglas ◽  
Gem Mackenroth ◽  
Andrew Swayne ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
Cell Therapy ◽  
Clinical Improvement ◽  
Epstein Barr Virus ◽  
T Cell Therapy ◽  
Sustained Improvement ◽  
Barr Virus ◽  
Cell Immunity ◽  
Epstein Barr

Background: Increasing evidence indicates a role for Epstein–Barr virus (EBV) in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the central nervous system because of defective cytotoxic CD8+ T cell immunity. We have previously reported results of a phase I clinical trial of autologous EBV-specific T cell therapy in MS 6 months after treatment.Objective: To investigate longer-term outcomes in MS patients who received autologous EBV-specific T cell therapy.Methods: We assessed participants 2 and 3 years after completion of T cell therapy.Results: We collected data from all 10 treated participants at year 2 and from 9 participants at year 3. No serious treatment-related adverse events were observed. Four participants had at least some sustained clinical improvement at year 2, including reduced fatigue in three participants, and reduced Expanded Disability Status Scale score in two participants. Three participants experienced a sustained improvement in at least some symptoms at year 3. More sustained improvement was associated with higher EBV-specific CD8+ T cell reactivity in the administered T cell product.Conclusion: Autologous EBV-specific T cell therapy is well-tolerated, and some degree of clinical improvement can be sustained for up to 3 years after treatment.

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