SPECIFIC CYTOTOXIC T-LYMPHOCYTES RECOGNIZE THE IMMEDIATE-EARLY TRANSACTIVATOR ZTA OF EPSTEIN-BARR-VIRUS

We identified the immediate-early transactivator Zta of Epstein-Barr v irus as a target for specific cytotoxic T lymphocytes (CTL). Cells pul sed with overlapping synthetic peptides representing the entire amino acid sequence of Zta proved to be efficient for the in vitro stimulati on of Zta-specific CTL in several donors. With peptide-pulsed target c ells, we found that CTL from several donors recognize a peptide compri sing 15 amino acids. The immune response against this peptide exerted by CTL lines from different donors was found to be restricted by two d ifferent molecules of the major histocompatibility complex: HLA-BS aci d BLA-Cw6. The latter molecule could for the first time be identified as a restricting element for a CTL response. The epitope of the HLA-Bg -restricted CTL could be mapped to an octameric sequence between amino acid positions 190 and 197 of the Zta protein, whereas the minimal ep itope of HLA-Cw6-restricted CTL consists of 11 to 15 residues between positions 187 and 201. Thus, the HLA-B8 and HLA-Cw6 epitopes widely ov erlap but are not completely identical. In vitro stimulation of blood lymphocytes from a panel of HLA-B8-positive or HLA-Cw6-positive virus carriers, using autologous cells pulsed with the Zta peptides comprisi ng the HLA-BS or HLA-Cw6 epitope, respectively, revealed in both cases that most of these donors developed a Zta-specific cytotoxic activity . These data, as well as the high spread of the major histocompatibili ty complex molecules HLA-Bg and HLA-Cw6 in most populations, suggest t hat an efficient CTL response directed against gene products of the im mediate-early group of the lytic cycle exists in vivo in a considerabl e portion of virus carriers. A CTL response against proteins expressed immediately after the switch into the lyric cycle could eliminate lyt ically activated cells at an early stage and would thus efficiently pr event the production and release of progeny virions.