Mapping of B and T Cell Epitopes on the Epstein-Barr Virus Receptor Ligand Gp340: A Candidate Subunit Vaccine

Epstein-Barr virus is a very common human virus that infects 90% of human adults. EBV replicates in epithelial and B cells and causes infectious mononucleosis. EBV infection is also linked to various cancers, including Burkitt’s lymphoma and nasopharyngeal carcinomas, and autoimmune diseases such as multiple sclerosis. Currently, there are no effective drugs or vaccines to treat or prevent EBV infection. Herein, we applied a computer-aided strategy to design a prophylactic epitope vaccine ensemble from experimentally defined T and B cell epitopes. Such strategy relies on identifying conserved epitopes in conjunction with predictions of HLA presentation for T cell epitope selection and calculations of accessibility and flexibility for B cell epitope selection. The T cell component includes 14 CD8 T cell epitopes from early antigens and 4 CD4 T cell epitopes, targeted during the course of a natural infection and providing a population protection coverage of over 95% and 81.8%, respectively. The B cell component consists of 3 experimentally defined B cell epitopes from gp350 plus 4 predicted B cell epitopes from other EBV envelope glycoproteins, all mapping in flexible and solvent accessible regions. We discuss the rationale for the formulation and possible deployment of this epitope vaccine ensemble.

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Endogenous Presentation of CD8+ T Cell Epitopes from Epstein-Barr Virus–encoded Nuclear Antigen 1

Journal of Experimental Medicine ◽

10.1084/jem.20040191 ◽

2004 ◽

Vol 199 (10) ◽

pp. 1421-1431 ◽

Cited By ~ 104

Author(s):

Judy Tellam ◽

Geoff Connolly ◽

Katherine J. Green ◽

John J. Miles ◽

Denis J. Moss ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Antigen Processing ◽

Epstein Barr Virus ◽

Cd8 T Cell ◽

Nuclear Antigen ◽

T Cell Epitopes ◽

Barr Virus ◽

Degradation Rates ◽

Epstein Barr

Epstein-Barr virus (EBV)–encoded nuclear antigen (EBNA)1 is thought to escape cytotoxic T lymphocyte (CTL) recognition through either self-inhibition of synthesis or by blockade of proteasomal degradation by the glycine-alanine repeat (GAr) domain. Here we show that EBNA1 has a remarkably varied cell type–dependent stability. However, these different degradation rates do not correspond to the level of major histocompatibility complex class I–restricted presentation of EBNA1 epitopes. In spite of the highly stable expression of EBNA1 in B cells, CTL epitopes derived from this protein are efficiently processed and presented to CD8+ T cells. Furthermore, we show that EBV-infected B cells can readily activate EBNA1-specific memory T cell responses from healthy virus carriers. Functional assays revealed that processing of these EBNA1 epitopes is proteasome and transporter associated with antigen processing dependent. We also show that the endogenous presentation of these epitopes is dependent on the newly synthesized protein rather than the long-lived stable EBNA1. Based on these observations, we propose that defective ribosomal products, not the full-length antigen, are the primary source of endogenously processed CD8+ T cell epitopes from EBNA1.

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Proteasome inhibitors reconstitute the presentation of cytotoxic T-cell epitopes in Epstein-Barr virus-associated tumors

International Journal of Cancer ◽

10.1002/ijc.10653 ◽

2002 ◽

Vol 101 (6) ◽

pp. 532-538 ◽

Cited By ~ 28

Author(s):

Riccardo Gavioli ◽

Simona Vertuani ◽

Maria G. Masucci

Keyword(s):

T Cell ◽

Epstein Barr Virus ◽

Proteasome Inhibitors ◽

Cytotoxic T Cell ◽

T Cell Epitopes ◽

Barr Virus ◽

Epstein Barr ◽

Associated Tumors

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Identification of CD8+ T-Cell Epitopes Specific for Immediate-Early Transactivator Rta of Epstein-Barr Virus

Human Immunology ◽

10.1016/j.humimm.2005.01.017 ◽

2005 ◽

Vol 66 (5) ◽

pp. 483-493 ◽

Cited By ~ 4

Author(s):

Hongxiang Yu ◽

Nalini Srinivasan ◽

Eechee Ren ◽

Sohha Chan

Keyword(s):

T Cell ◽

Epstein Barr Virus ◽

Cd8 T Cell ◽

Immediate Early ◽

T Cell Epitopes ◽

Barr Virus ◽

Epstein Barr

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Defining the expression hierarchy of latent T-cell epitopes in Epstein-Barr virus infection with TCR-like antibodies

Scientific Reports ◽

10.1038/srep03232 ◽

2013 ◽

Vol 3 (1) ◽

Cited By ~ 10

Author(s):

Adrian Chong Nyi Sim ◽

Chien Tei Too ◽

Min Zin Oo ◽

Junyun Lai ◽

Michelle Yating Eio ◽

...

Keyword(s):

T Cell ◽

Virus Infection ◽

Epstein Barr Virus ◽

Epstein Barr Virus Infection ◽

T Cell Epitopes ◽

Barr Virus ◽

Epstein Barr ◽

Barr Virus Infection

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Immunoinformatic Analysis Reveals Antigenic Heterogeneity of Epstein-Barr Virus Is Immune-Driven

Frontiers in Immunology ◽

10.3389/fimmu.2021.796379 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ana Cirac ◽

Remy Poirey ◽

Michael Dieckmeyer ◽

Klaus Witter ◽

Henri-Jacques Delecluse ◽

...

Keyword(s):

T Cell ◽

Epstein Barr Virus ◽

Cd4 T Cell ◽

Immune Recognition ◽

T Cell Epitopes ◽

Barr Virus ◽

Data Mining Approach ◽

Epstein Barr ◽

Relationship Of ◽

The Impact

Whole genome sequencing of Epstein-Barr virus (EBV) isolates from around the world has uncovered pervasive strain heterogeneity, but the forces driving strain diversification and the impact on immune recognition remained largely unknown. Using a data mining approach, we analyzed more than 300 T-cell epitopes in 168 published EBV strains. Polymorphisms were detected in approximately 65% of all CD8+ and 80% of all CD4+ T-cell epitopes and these numbers further increased when epitope flanking regions were included. Polymorphisms in CD8+ T-cell epitopes often involved MHC anchor residues and resulted in changes of the amino acid subgroup, suggesting that only a limited number of conserved T-cell epitopes may represent generic target antigens against different viral strains. Although considered the prototypic EBV strain, the rather low degree of overlap with most other viral strains implied that B95.8 may not represent the ideal reference strain for T-cell epitopes. Instead, a combinatorial library of consensus epitopes may provide better targets for diagnostic and therapeutic purposes when the infecting strain is unknown. Polymorphisms were significantly enriched in epitope versus non-epitope protein sequences, implicating immune selection in driving strain diversification. Remarkably, CD4+ T-cell epitopes in EBNA2, EBNA-LP, and the EBNA3 family appeared to be under negative selection pressure, hinting towards a beneficial role of immune responses against these latency type III antigens in virus biology. These findings validate this immunoinformatics approach for providing novel insight into immune targets and the intricate relationship of host defense and virus evolution that may also pertain to other pathogens.

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Identification of two T-cell epitopes on the candidate Epstein-Barr virus vaccine glycoprotein gp340 recognized by CD4+ T-cell clones.

Journal of Virology ◽

10.1128/jvi.65.7.3821-3828.1991 ◽

1991 ◽

Vol 65 (7) ◽

pp. 3821-3828 ◽

Cited By ~ 26

Author(s):

L E Wallace ◽

J Wright ◽

D O Ulaeto ◽

A J Morgan ◽

A B Rickinson

Keyword(s):

T Cell ◽

Virus Vaccine ◽

Epstein Barr Virus ◽

Cd4 T Cell ◽

T Cell Epitopes ◽

T Cell Clones ◽

Barr Virus ◽

Cell Clones ◽

Epstein Barr

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T Cell Epitope Clustering in the Highly Immunogenic BZLF1 Antigen of Epstein-Barr Virus

Journal of Virology ◽

10.1128/jvi.02642-14 ◽

2014 ◽

Vol 89 (1) ◽

pp. 703-712 ◽

Cited By ~ 5

Author(s):

Melissa J. Rist ◽

Michelle A. Neller ◽

Jacqueline M. Burrows ◽

Scott R. Burrows

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Cell Response ◽

Epstein Barr Virus ◽

T Cell Response ◽

T Cell Epitopes ◽

Barr Virus ◽

Epstein Barr ◽

Hla Molecules

ABSTRACTPolymorphism in the human leukocyte antigen (HLA) loci ensures that the CD8+T cell response to viruses is directed against a diverse range of antigenic epitopes, thereby minimizing the impact of virus escape mutation across the population. The BZLF1 antigen of Epstein-Barr virus is an immunodominant target for CD8+T cells, but the response has been characterized only in the context of a limited number of HLA molecules due to incomplete epitope mapping. We have now greatly expanded the number of defined CD8+T cell epitopes from BZLF1, allowing the response to be evaluated in a much larger proportion of the population. Some regions of the antigen fail to be recognized by CD8+T cells, while others include clusters of overlapping epitopes presented by different HLA molecules. These highly immunogenic regions of BZLF1 include polymorphic sequences, such that up to four overlapping epitopes are impacted by a single amino acid variation common in different regions of the world. This focusing of the immune response to limited regions of the viral protein could be due to sequence similarity to human proteins creating “immune blind spots” through self-tolerance. This study significantly enhances the understanding of the immune response to BZLF1, and the precisely mapped T cell epitopes may be directly exploited in vaccine development and adoptive immunotherapy.IMPORTANCEEpstein-Barr virus (EBV) is an important human pathogen, associated with several malignancies, including nasopharyngeal carcinoma and Hodgkin lymphoma. T lymphocytes are critical for virus control, and clinical trials aimed at manipulating this arm of the immune system have demonstrated efficacy in treating these EBV-associated diseases. These trials have utilized information on the precise location of viral epitopes for T cell recognition, for either measuring or enhancing responses. In this study, we have characterized the T cell response to the highly immunogenic BZLF1 antigen of EBV by greatly expanding the number of defined T cell epitopes. An unusual clustering of epitopes was identified, highlighting a small region of BZLF1 that is targeted by the immune response of a high proportion of the world's population. This focusing of the immune response could be utilized in developing vaccines/therapies with wide coverage, or it could potentially be exploited by the virus to escape the immune response.

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