Lipidation of T helper sequences from hepatitis C virus core significantlyenhances T-cell activity in vitro

Successful elimination of the hepatitis C virus (HCV) during acute infectio n has been linked to strong HCV-specific in vitro T-cell proliferation, whe reas T cells from patients with chronic hepatitis C respond only weakly to HCV antigens. Lipid-coupled peptides are immunostimulants, which might prov ide a basis for novel therapeutic strategies against HCV. Therefore, in 20 patients with chronic hepatitis C, we studied whether tri-palmitoyl-S-cyste ine-coupled peptides could modify in vitro T-cell proliferation (by [H-3]th ymidine uptake) in response to virus core and NS4. The lipopeptides corresp onded to five immunodominant T helper epitopes of HCV core. Contrary to unm odified peptides, the lipopeptides specifically enhanced [H-3]thymidine upt ake in response to HCV antigens but not to a non-HCV related control antige n. They increased the frequency of responders (stimulation index, SI greate r than or equal to4) to core (13/20 versus 2/20; p = 0.0008) and NS4 (20/20 versus 7/20; p < 0.0001) among our patients with chronic hepatitis C. This immunostimulatory effect was dose-dependent, and was observed specifically with lipopeptides corresponding to the HCV epitopes. Our data demonstrate that the poor in vitro T-cell proliferation of patients with chronic hepati tis C can be improved when T cells are co-stimulated with HCV core-derived T helper lipopeptides, while the same peptides in unlipidated form had no e ffects. Thus, lipopeptides corresponding to HCV T-cell epitopes may offer n ovel immunomodulatory strategies against HCV.