ANTIVIRAL PROTECTION CONFERRED BY RECOMBINANT ADENYLATE-CYCLASE TOXINS FROM BORDETELLA-PERTUSSIS CARRYING A CD8(-CELL EPITOPE FROM LYMPHOCYTIC CHORIOMENINGITIS VIRUS() T)

The elucidation of the mechanisms of antigen presentation by major his tocompatibility complex class I molecules has stimulated the search fo r nonreplicative vectors that could deliver CD8(+) T cell epitopes to the cytosol of antigen-presenting cells to trigger the activation of s pecific cytotoxic T lymphocytes (CTLs) in vivo. In the present study, we investigated the potential ability of an invasive adenylate cyclase toxin from Bordetella pertussis, carrying a CD8(+) T cell epitope fro m the nucleoprotein of lymphocyte choriomeningitis virus (LCMV), to st imulate protective anti-viral immunity. Mice immunized with this recom binant toxin developed strong CTL responses against LCMV-infected targ et cells, Moreover, these mice were protected against an intracerebral challenge with a virulent strain of LCMV that killed all nonimmunized mice within 7 days, This protection was abolished after in vivo elimi nation of CD8(+) T cells, A mutant toxin devoid of adenylate cyclase a ctivity (i,e,, cAMP synthesizing activity) was constructed by insertio n of a dipeptide into the catalytic site of the molecule, This genetic ally detoxified invasive toxin carrying the LCMV epitope stimulated a strong CTL response against both peptide-coated and virus-infected tar get cells, and mice immunized with this molecule were fully protected against a lethal intracerebral LCMV challenge. To our knowledge, this study represents the first demonstration that a genetically detoxified bacterial toxin carrying a viral CTL epitope can stimulate efficient protective immunity.