Protection against lymphocytic choriomeningitis virus infection induced bya reduced peptide bond analogue of the H-2D(b)-restricted CD8(+) T cell epitope GP33

Recent investigations have suggested that pseudopeptides containing modifie d peptide bonds might advantageously replace natural peptides in therapeuti c strategies. We have generated eight reduced peptide bond psi(CH2-NH) anal ogues corresponding to the H-2D(b)-restricted CD8(+) T cell epitope (called GP33) of the glycoprotein of the lymphocytic choriomeningitis virus. One o f these pseudopeptides, containing a reduced peptide bond between residues 6 and 7 (psi(6-7)), displayed very similar properties of binding to major h istocompatibility complex (MHC) and recognition by T cell receptor transgen ic T cells specific for GP33 when compared with the parent peptide. We asse ssed in vitro and in vivo the proteolytic resistance of GP33 and psi(6-7) a nd analyzed its contribution to the priming properties of these peptides. T he psi(6-7) analogue exhibited a dramatically increased proteolytic resista nce when compared with GP33, and we show for the first time that MHC-peptid e complexes formed in vivo with a pseudopeptide display a sustained half-li fe compared with the complexes formed with the natural peptide. Furthermore , in contrast to immunizations with GP33, three injections of psi(6-7) in s aline induced significant antiviral protection in mice. The enhanced abilit y of psi(6-7) to induce antiviral protection may result from the higher sta bility of the analogue and/or of the MHC-analogue complexes.