Selective amino acid substitutions of a subdominant Epstein-Barr virus LMP2-derived epitope increase HLA/peptide complex stability and immunogenicity: Implications for immunotherapy of Epstein-Barr virus-associated malignancies

Fabiola Micheletti, Remo Guerrini, Annarita Formentin, Alessandro Canella, Mauro Marastoni, Martina Bazzaro, Roberto Tomatis, Serena Traniello, Riccardo Gavioli

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

The latent membrane protein 2 is an immunogenic antigen expressed in Epstein-Barr virus (EBV)-associated tumors and consequently it may represent a target for specific cytotoxic T lymphocyte (CTL)-based immunotherapies. However, the efficacy of such a therapy is limited by the poor immunogenicity of the protein that induces weak CTL responses directed to the CLGGLLTMV (CLG) epitope only in the minority of EBV-seropositive donors. We have now demonstrated that selective peptide stimulation of peripheral blood lymphocytes induced CLG-specific CTL in all donors, suggesting that this epitope can be a suitable target for specific immunotherapies. We found that the CLG peptide has a low affinity for HLA-A(*)0201 and does not produce stable complexes, both factors that are likely to determine the strength of CTL responses to this epitope. Therefore, we synthesized and tested CLG analogues carrying single or combined amino acid substitutions to increase HLA/peptide stability. Among the analogues tested we identified two peptides which, compared to the natural epitope, showed higher affinity for HLA-A(*)0201 molecules, and produced stable complexes. These peptides demonstrated a potent, specific stimulatory capacity and could be used for selective CTL-based therapies.

Original languageEnglish (US)
Pages (from-to)2579-2589
Number of pages11
JournalEuropean Journal of Immunology
Volume29
Issue number8
DOIs
StatePublished - 1999

Keywords

  • Cytotoxic T lymphocyte
  • Epitope
  • Epstein-Barr virus
  • HLA class I

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