LONG-LASTING ANTIVIRAL CYTOTOXIC T-LYMPHOCYTES INDUCED IN-VIVO WITH CHIMERIC-MULTIRESTRICTED LIPOPEPTIDES

Cytotoxic T lymphocytes (CTL) play a major role in protective immunity against viral diseases. However, the antigenic formulations that can be used in vaccinations able to generate virus-specific CTL responses in vivo have yet to be defined. We have previously shown that HIV-1-sp ecific CTL can be elicited in mice by injecting without adjuvant a syn thetic peptide of the envelope glycoprotein that has been modified by the addition of a simple lipid tail to the end of the sequence (lipope ptide). The present study set out to address the question of whether s uch immunogens may be appropriate for preparing a human synthetic vacc ine. We first showed that CTL were effectively induced by lipopeptides when given s.c. or i.p. We evidenced that the in vivo induction requi red stimulation of a concomitant specific T helper cell response, impl ying the presence of at least one CD4 epitope in the synthetic sequenc e used. Bearing in mind the particular properties that would be requir ed in a prospective human peptide vaccine, we conceived a strategy in which a virus-specific CTL response could be generated in mice of diff erent haplotypes using a single lipopeptide. We therefore tested a lip opeptide construct that integrated a synthetic sequence having three c olinear epitopes of the influenza virus nucleoprotein, each restricted to a different H-2 haplotype. We found that a CTL response could be e licited to all three epitopes of this chimeric multirestricted lipopep tide construct. Finally, we have attempted to estimate the duration of the responses; strong CTL activities were still present up to six mon ths after the last injection. These findings indicate that this approa ch may be suitable for developing a synthetic vaccine for human use.