Identification of a naturally processed HLA-DR-restricted T-helper epitope in Epstein-Barr virus nuclear antigen type 1

J Immunother. May-Jun 2003;26(3):212-21. doi: 10.1097/00002371-200305000-00005.

Abstract

Epstein-Barr virus nuclear antigen type 1 (EBNA1), the only viral protein that is unequivocally expressed in all Epstein-Barr virus (EBV)-associated malignant diseases, is essential for viral DNA replication and maintenance of the viral episome in infected cells. A glycine-alanine repeat domain inhibits antigen processing through the ubiquitin-proteasome pathway for presentation on human leukocyte antigen (HLA) class I molecules. EBNA1 is not protected from the HLA class II processing pathway, and CD4+ HLA class II-restricted T cells recognize the antigen. CD4+ T-helper (Th) cells play critical roles in initiating, regulating, and maintaining immune responses against viral infections and tumors, so that inclusion of EBNA1 as a target antigen may improve immunotherapy for EBV-associated cancers. In this study, the authors used the TEPITOPE software program to predict promiscuous class II epitope candidates. After several HLA-DR-restricted peptides were identified by in vitro analysis of the T-cell response to synthetic peptides, a T-cell clone was established that was specific for one of the peptides. Functional studies were performed with this clone. The CD4+ T helper cells specific for the HLA-DR15-restricted peptide EBNA1(482) (AEGLRALLARSHVER) recognized naturally processed EBNA1 protein. This epitope was presented by several HLA-DR alleles, including DR4, DR7, and DR11. The inclusion of the promiscuous, naturally processed EBNA1(482) epitope in vaccine constructs could enhance immune responses against EBV-positive cancers.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Line
  • Epitopes, T-Lymphocyte*
  • Epstein-Barr Virus Nuclear Antigens / immunology*
  • HLA-DR Antigens / genetics
  • HLA-DR Antigens / immunology*
  • Humans
  • Molecular Sequence Data

Substances

  • Epitopes, T-Lymphocyte
  • Epstein-Barr Virus Nuclear Antigens
  • HLA-DR Antigens
  • EBV-encoded nuclear antigen 1