Lipidation of T helper sequences from hepatitis C virus core significantly enhances T-cell activity in vitro.
Successful elimination of the hepatitis C virus (HCV) during acute infection has been linked to strong HCV-specific in vitro T-cell proliferation, whereas T cells from patients with chronic hepatitis C respond only weakly to HCV antigens. Lipid-coupled peptides are immunostimulants, which might provide a basis for novel therapeutic strategies against HCV. Therefore, in 20 patients with chronic hepatitis C, we studied whether tri-palmitoyl-S-cysteine-coupled peptides could modify in vitro T-cell proliferation (by [3H]thymidine uptake) in response to virus core and NS4. The lipopeptides corresponded to five immunodominant T helper epitopes of HCV core. Contrary to unmodified peptides, the lipopeptides specifically enhanced [3H]thymidine uptake in response to HCV antigens but not to a non-HCV related control antigen. They increased the frequency of responders (stimulation index, SI > or = 4) 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 hepatitis 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 effects. Thus, lipopeptides corresponding to HCV T-cell epitopes may offer novel immunomodulatory strategies against HCV.
Langhans
B
B
Department of General Internal Medicine, University of Bonn, Bonn, Germany.
Braunschweiger
I
I
Schweitzer
S
S
Jung
G
G
Inchauspé
G
G
Sauerbruch
T
T
Spengler
U
U
D000328:Adult; D018929:Cell Culture Techniques; D002455:Cell Division / Q000276:immunology; D003545:Cysteine / Q000031:analogs & derivatives / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D016174:Hepacivirus / Q000276:immunology; D018936:Hepatitis C Antigens / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014758:Viral Core Proteins / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D018936:Hepatitis C Antigens; C093542:NS4 protein, hepatitis C virus; D010446:Peptide Fragments; D014758:Viral Core Proteins; D017361:Viral Nonstructural Proteins; C069130:nucleocapsid protein, Hepatitis C virus; C038837:tripalmitoyl cysteine; D003545:Cysteine