scholarly journals Different HLA-B27 subtypes present the same immunodominant Epstein-Barr virus peptide.

1993 ◽  
Vol 178 (3) ◽  
pp. 879-887 ◽  
Author(s):  
J M Brooks ◽  
R J Murray ◽  
W A Thomas ◽  
M G Kurilla ◽  
A B Rickinson
Keyword(s):  
Epstein Barr Virus ◽  
Cytotoxic T Lymphocyte ◽  
Strong Association ◽  
Peptide Binding ◽  
Nuclear Antigen ◽  
Peptide Motif ◽  
Hla B27 ◽  
Barr Virus ◽  
Epstein Barr ◽  
Ctl Responses

An immunological basis has been postulated for the strong association between at least five subtypes of the HLA-B27 allele (B27.01, .02, .04, .05, and .06) and ankylosing spondylitis, namely that cytotoxic T lymphocyte (CTL) responses are induced against an "arthritogenic" peptide that these different subtypes can all present. This requires a degree of overlap between the peptide binding repertoires of different B27 molecules. The present work, using CTL responses to Epstein-Barr virus (EBV) as a model system in which to identify B27-restricted epitopes, provides the first direct evidence that different disease-related alleles can present the same immunodominant peptide. We first noted that EBV-specific CTL clones, whether from B27.05-, B27.02-, or B27.04-positive donors, were largely subtype-specific in their restriction, recognizing only EBV-transformed B cell lines of the relevant B27 subtype. However, when tested against targets expressing individual EBV proteins from recombinant vaccinia virus vectors, all B27.05-restricted, all B27.02-restricted, and a proportion of B27.04-restricted clones were reactive to the same viral nuclear antigen, Epstein-Barr nuclear antigen (EBNA)3C. In subsequent peptide sensitization assays, all the EBNA3C-specific clones tested and also the EBNA3C-specific component within polyclonal CTL preparations from B27.05-, B27.02-, or B27.04-positive donors recognized the same immunodominant viral peptide RRIYDLIEL (EBNA3C residues 258-266). This sequence accords well with the proposed B27.05 peptide motif and clearly must be accommodated within the different peptide binding grooves of B27.05, B27.02, and B27.04 molecules. Clonal analysis revealed a second component of the B27.04-restricted response that was not shared with other subtypes. This was directed against an EBV latent membrane protein LMP2 epitope whose sequence RRRWRRLTV satisfies some but not all requirements of the B27.05 peptide motif. We conclude that there is indeed a degree of functional overlap between different B27 subtypes in their selection and presentation of CTL epitopes.

scholarly journals T cell responses and virus evolution: loss of HLA A11-restricted CTL epitopes in Epstein-Barr virus isolates from highly A11-positive populations by selective mutation of anchor residues.

1994 ◽  
Vol 179 (4) ◽  
pp. 1297-1305 ◽  
Author(s):  
P O de Campos-Lima ◽  
V Levitsky ◽  
J Brooks ◽  
S P Lee ◽  
L F Hu ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Cytotoxic T Lymphocyte ◽  
Virus Evolution ◽  
Nuclear Antigen ◽  
Ctl Epitopes ◽  
Barr Virus ◽  
Southern Chinese ◽  
Epstein Barr ◽  
Ctl Responses

Epstein-Barr virus (EBV) is a B lymphotropic herpesvirus of humans that elicits strong HLA class I-restricted cytotoxic T lymphocyte (CTL) responses. An influence of such responses on virus evolution was first suggested by our finding that EBV isolates from the highly HLA A11-positive Papua New Guinea (PNG) population carried a lys-thr mutation at residue 424 of the nuclear antigen EBV-encoded nuclear antigen (EBNA4) that destroyed the immunodominant target epitope for A11-restricted CTL recognition. Here we turn to a much larger population, Southern Chinese, where the A11 allele is again present in over 50% of the individuals. Each of 23 EBV isolates analyzed from this population were also mutated in the EBNA4 416-424 epitope, the mutations selectively involving one of the two anchor residues in positions 2 (417 val-leu) or 9 (424 lys-asp, -arg or -thr) that are critical for A11-peptide interaction. The majority of the Chinese isolates and all 10 PNG isolates also carried mutations affecting positions 1 and 2 of the next most immunodominant A11-restricted epitope, EBNA4 residues 399-408. These changes clearly affected antigenicity since A11-positive lymphoblastoid cell lines (LCLs) carrying these mutant EBV strains were not recognized by A11-restricted CTLs raised against the prototype B95.8 virus. Furthermore, Chinese donors naturally infected with these mutant viruses did not mount detectable A11-restricted CTL responses on in vitro stimulation with autologous LCL cells carrying either the B95.8 or their endogenous EBV strain. In two different highly A11-positive populations, therefore, immune pressure appears to have selected for resident EBV strains lacking immunodominant A11-restricted CTL epitopes.

scholarly journals Characterization of an human leucocyte antigen A2-restricted Epstein-Barr virus nuclear antigen-1-derived cytotoxic T-lymphocyte epitope

Immunology ◽  
2010 ◽  
Vol 129 (3) ◽  
pp. 386-395 ◽  
Author(s):  
Diego Marescotti ◽  
Federica Destro ◽  
Anna Baldisserotto ◽  
Mauro Marastoni ◽  
Giuseppe Coppotelli ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Epstein Barr Virus ◽  
Human Leucocyte Antigen ◽  
Cytotoxic T Lymphocyte ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals Inhibition of Antigen Presentation by the Glycine/Alanine Repeat Domain Is Not Conserved in Simian Homologues of Epstein-Barr Virus Nuclear Antigen 1

1999 ◽  
Vol 73 (9) ◽  
pp. 7381-7389 ◽  
Author(s):  
Neil W. Blake ◽  
Amir Moghaddam ◽  
Pasupuleti Rao ◽  
Amitinder Kaur ◽  
Rhona Glickman ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Antigen Processing ◽  
Epstein Barr Virus ◽  
Cytotoxic T Lymphocyte ◽  
Nuclear Antigen ◽  
Old World ◽  
Barr Virus ◽  
Epstein Barr ◽  
Antigen Processing And Presentation

ABSTRACT Most humans and Old World nonhuman primates are infected for life with Epstein-Barr virus (EBV) or closely related gammaherpesviruses in the same lymphocryptovirus (LCV) subgroup. Several potential strategies for immune evasion and persistence have been proposed based on studies of EBV infection in humans, but it has been difficult to test their actual contribution experimentally. Interest has focused on the EBV nuclear antigen 1 (EBNA1) because of its essential role in the maintenance and replication of the episomal viral genome in latently infected cells and because EBNA1 endogenously expressed in these cells is protected from presentation to the major histocompatibility complex class-I restricted cytotoxic T-lymphocyte (CTL) response through the action of an internal glycine-alanine repeat (GAR). Given the high degree of biologic conservation among LCVs which infect humans and Old World primates, we hypothesized that strategies essential for viral persistence would be well conserved among viruses of this subgroup. We show that the rhesus LCV EBNA1 shares sequence homology with the EBV and baboon LCV EBNA1 and that the rhesus LCV EBNA1 is a functional homologue for EBV EBNA1-dependent plasmid maintenance and replication. Interestingly, all three LCVs possess a GAR domain, but the baboon and rhesus LCV EBNA1 GARs fail to inhibit antigen processing and presentation as determined by using three different in vitro CTL assays. These studies suggest that inhibition of antigen processing and presentation by the EBNA1 GAR may not be an essential mechanism for persistent infection by all LCV and that other mechanisms may be important for immune evasion during LCV infection.

scholarly journals The B Subunit of Escherichia coli Heat-Labile Enterotoxin Enhances CD8+ Cytotoxic-T-Lymphocyte Killing of Epstein-Barr Virus-Infected Cell Lines

2003 ◽  
Vol 77 (7) ◽  
pp. 4298-4305 ◽  
Author(s):  
Kong-Wee Ong ◽  
A. Douglas Wilson ◽  
Timothy R. Hirst ◽  
Andrew J. Morgan
Keyword(s):  
Cell Lines ◽  
Epstein Barr Virus ◽  
Cytotoxic T Lymphocyte ◽  
Hla Class I ◽  
Class I ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
B Subunit ◽  
Histocompatibility Complex ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) is associated with a number of important human cancers, including nasopharyngeal carcinoma, gastric carcinoma, and Hodgkin's lymphoma. These tumors express a viral nuclear antigen, EBV nuclear antigen 1 (EBNA1), which cannot be presented to T cells in a major histocompatibility complex class I context, and the viral latent membrane proteins (LMPs). Although the LMPs are expressed in these tumors, no effective immune response is made. We report here that exposure to the cholera-like enterotoxin B subunit (EtxB) in EBV-infected lymphoblastoid cell lines (LCLs) enhances their susceptibility to killing by LMP-specific CD8+ cytotoxic T lymphocytes (CTLs) in a HLA class I-restricted manner. CTL killing of LCLs is dramatically increased through both transporter-associated protein-dependent and -independent epitopes after EtxB treatment. The use of mutant B subunits revealed that the enhanced susceptibility of LCLs to CTL killing is dependent on the B subunit's interaction with GM1 but not its signaling properties. These important findings could underpin the development of novel approaches to treating EBV-associated malignancies and may offer a general approach to increasing the presentation of other tumor and viral antigens.

scholarly journals HLA-A11-Restricted Epitope Polymorphism among Epstein-Barr Virus Strains in the Highly HLA-A11-Positive Chinese Population: Incidence and Immunogenicity of Variant Epitope Sequences

2003 ◽  
Vol 77 (21) ◽  
pp. 11507-11516 ◽  
Author(s):  
R. S. Midgley ◽  
A. I. Bell ◽  
Q. Y. Yao ◽  
D. Croom-Carter ◽  
A. D. Hislop ◽  
...  
Keyword(s):  
Chinese Population ◽  
Epstein Barr Virus ◽  
Cytotoxic T Lymphocyte ◽  
Nuclear Antigen ◽  
Sequence Variants ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT An individual's CD8+-cytotoxic-T-lymphocyte (CTL) response to Epstein-Barr virus (EBV) latent cycle antigens focuses on a small number of immunodominant epitopes often presented by just one of the available HLA class I alleles; for example, HLA-A11-positive Caucasians frequently respond to two immunodominant HLA A11 epitopes, IVTDFSVIK (IVT) and AVFDRKSDAK (AVF), within the nuclear antigen EBNA3B. Here, we reexamine the spectrum of EBV strains present in the highly HLA-A11-positive Chinese population for sequence changes in these epitopes relative to the Caucasian type 1 prototype strain B95.8. The IVT epitope was altered in 61 of 64 Chinese type 1 viruses, with four different sequence variants being observed, and the AVF epitope was altered in 46 cases with six different sequence variants; by contrast, all 10 Chinese type 2 viruses retained the prototype 2 epitope sequences. All but one of the type 1 epitope variants were poorly recognized by IVT- or AVF-specific CTLs in pulse-chase assays of peptide-mediated target cell lysis. More importantly, we screened HLA-A11-positive Chinese donors carrying viruses with known epitope mutations for evidence of epitope-specific CTL memory by enzyme-linked immunospot assays: none of the type 1 variants tested, nor the type 2 prototype, appeared to be immunogenic in vivo. The data remain consistent with the possibility that, during virus-host coevolution, pressure from the host CTL-mediated immune response has given A11 epitope-loss viruses a selective advantage.

scholarly journals Multiple HLA A11-restricted cytotoxic T-lymphocyte epitopes of different immunogenicities in the Epstein-Barr virus-encoded nuclear antigen 4.

1993 ◽  
Vol 67 (3) ◽  
pp. 1572-1578 ◽  
Author(s):  
R Gavioli ◽  
M G Kurilla ◽  
P O de Campos-Lima ◽  
L E Wallace ◽  
R Dolcetti ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Epstein Barr Virus ◽  
Cytotoxic T Lymphocyte ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals The life span of major histocompatibility complex-peptide complexes influences the efficiency of presentation and immunogenicity of two class I-restricted cytotoxic T lymphocyte epitopes in the Epstein-Barr virus nuclear antigen 4.

1996 ◽  
Vol 183 (3) ◽  
pp. 915-926 ◽  
Author(s):  
V Levitsky ◽  
Q J Zhang ◽  
J Levitskaya ◽  
M G Masucci
Keyword(s):  
Cell Surface ◽  
T Lymphocyte ◽  
Epstein Barr Virus ◽  
Cytotoxic T Lymphocyte ◽  
Class I ◽  
Nuclear Antigen ◽  
Ctl Epitopes ◽  
Barr Virus ◽  
Wide Range ◽  
Epstein Barr

We have investigated the reactivity to two human histocompatibility leukocyte antigen (HLA) A11-restricted cytotoxic T lymphocyte (CTL) epitopes derived from amino acids 416-424 (IVTDFSVIK, designated IVT) and 399-408 (AVFDRKSVAK, designated AVF) of the Epstein-Barr virus (EBV) nuclear antigen (EBNA) 4. A strong predominance of CTL clones specific for the IVT epitope was demonstrated in polyclonal cultures generated by stimulation of lymphocytes from the EBV-seropositive donor BK with the autologous B95.8 virus-transformed lymphoblastoid cell line (LCL). This was not due to intrinsic differences of CTL efficiency since clones specific for the two epitopes lysed equally well A11-positive phytohemagglutinin blasts and LCLs pulsed with the relevant synthetic peptide. Irrespective of the endogenous levels of EBNA4 expression, untreated LCLs were lysed more efficiently by the IVT-specific effectors, suggesting that a higher density of A11-IVT complexes is presented at the cell surface. In accordance, 10-50-fold higher amounts of IVT peptides were found in high-performance liquid chromatography fractions of acid extracts corresponding to an abundance of about 350-12,800 IVT and 8-760 AVF molecules per cell. Peptide-mediated competition of CTL sensitization, transport assays in streptolysin-O permeabilized cells, and induction of A11 expression in the transporter associated with antigen presentation-deficient T2/A11 transfectant demonstrated that the IVT and AVF peptides bind with similar affinities to A11, are translocated with equal efficiency to the endoplasmic reticulum, and form complexes of comparable stability over a wide range of temperature and pH conditions. A rapid surface turnover of A11 molecules containing the AVF peptide was demonstrated in metabolically active T2/A11 cells corresponding to a half-life of approximately 3.5 as compared to approximately 2 h for molecules induced at 26 degrees C in the absence of exogenous peptides and >12 h for IVT-containing complexes. This difference in persistence is likely to determine the representation of individual class I-restricted CTL epitopes within the cell surface pool of molecules, and may be an important factor contributing to their immunogenicity.

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