Nonresponsiveness to an immunodominant Epstein-Barr virus-encoded cytotoxic T-lymphocyte epitope in nuclear antigen 3A: implications for vaccine strategies.

An immunodominant Epstein-Barr virus (EBV)-encoded cytotoxic T lymphocyte (CTL) epitope has been mapped to the EBV nuclear antigen 3A. The epitope, represented by the peptide sequence AWNAGFLRGRAYGLD (hereafter termed AWNA), is restricted through the HLA-B8 allele and is expressed by type A but not type B-infected transformants. Herein, we show that EBV-specific memory CTLs from an HLA-B8+ healthy virus carrier, JS, did not respond in vitro to AWNA, even though that individual's endogenously infected transformants processed and presented the natural equivalent of this peptide to AWNA-specific CTLs from another B8+ individual. Instead, an epitope, represented by the peptide sequence QLSDTPLIPLTIFVGENTGV, was the dominant EBV-specific CTL epitope in donor JS. This epitope mapped to EBV nuclear antigen 2A, was restricted by an HLA-A2 subtype, and specifically associated with type A strains of EBV. No AWNA-specific CTL precursors were detected by limiting dilution analysis of peripheral blood mononuclear cells from donor JS whereas the precursor frequency of AWNA-specific CTLs from a responder donor, LC, was estimated at 1:4500. The presentation in vivo of an immunogenic epitope-HLA antigen complex is clearly insufficient to guarantee an effective memory CTL response to that foreign epitope. Thus, vaccination strategies based on peptides inducing CTL responses may need to take into account not only the polymorphism of HLA antigens but also possible allelic variation in the repertoires of T-cell receptors.