Molecularly defined
vaccine formulations capable of inducing
antiviral CD8+ T-cell-specific immunity in a manner compatible with human delivery are limited. Few molecules achieve this target without the support of an appropriate
immunological adjuvant. In this study, we investigate the potential of totally synthetic palmitoyl-tailed helper-cytotoxic-T-lymphocyte chimeric
epitopes (Th-CTL chimeric
lipopeptides) to induce herpes simplex virus type 1 (HSV-1)-specific CD8+ T-cell responses. As a model
antigen, the HSV-1
glycoprotein B498-505 (gB498-505) CD8+ CTL
epitope was synthesized in line with the Pan DR
peptide (PADRE), a universal CD4+ Th
epitope. The
peptide backbone, composed solely of both
epitopes, was extended by N-terminal attachment of one (PAM-Th-CTL), two [(PAM)2-Th-CTL], or three [(PAM)3-Th-CTL] palmitoyl lysines and delivered to H2b mice in adjuvant-free saline. Potent HSV-1 gB498-505-specific
antiviral CD8+ T-cell effector type 1 responses were induced by each of the palmitoyl-tailed Th-CTL chimeric
epitopes, irrespective of the number of
lipid moieties. The palmitoyl-tailed Th-CTL chimeric
epitopes provoked cell surface expression of major histocompatibility complex and costimulatory molecules and production of
interleukin-12 and
tumor necrosis factor alpha proinflammatory
cytokines by immature dendritic cells. Following ocular HSV-1 challenge, palmitoyl-tailed Th-CTL-immunized mice exhibited a decrease of virus replication in the eye and in the local trigeminal ganglion and reduced herpetic
blepharitis and corneal
scarring. The rational of the molecularly defined
vaccine approach presented in this study may be applied to ocular herpes and other
viral infections in humans, providing steps are taken to include appropriate Th and CTL
epitopes and
lipid groups.