Role of the specific T-cell response for clearance and control of hepatitis C virus

T cells are believed to be the main players in antiviral defence. To invest igate the role of the specific CD4+ T cell response for clearance and contr ol of the hepatitis C virus we studied patients with acute hepatitis C (AHC ) during the phase of spontaneous viral clearance and during follow up afte r elimination of the virus and resolution of disease. Symptomatic AHC has a self-limited course in 50% of patients, whereas the other half show virus persistence and develop chronic course of disease. Patients who were able t o mount a vigorous, polyclonal, multispecific, Till lymphokine dominated CD 4+ T-cell response showed viral clearance and a self-limited course of dise ase. In contrast, absence of this T-cell response in patients with AHC inva riably led to viral persistence and chronic hepatitis, The characteristics of the T-cell response were as follows: it was mainly directed against nons tructural proteins of the virus, it was multispecific and demonstrated immu nodominant epitopes, and the majority of T-cell clones established from our patients responded to a single peptide (NS3 aminoacid 1248-1261) within th e helicase region of HCV. Presentation of the peptide was HLA DR specific, the peptide showed promiscous binding, and it had high binding affinity to 10 of the most common 13 HLA DR alleles, thus patients with diverse HLA DR backgrounds could mount an immune response, Furthermore, the epitope was co nserved in 100% of 33 HCV strains published in databases, This strong initi al CD4+ T-cell response is not sufficient for a definitive recovery from AH C, it has to be maintained to control the hepatitis C virus, Loss of the re sponse after initial resolution of disease is followed by relapse, Even 20 years after an episode of self-limited AI-IC with elimination of HCV, we ha ve observed a significant virus-specific CD4+ T-cell response, Our data ind icate the decisive role of the virus-specific CD4+ T-cell response for clea rance and control of HCV, and contribute to our understanding of immune mec hanisms by which the host defends the HCV virus, This is a prerequisite for the development of new strategies to efficiently defend the virus by manip ulating or modulating the immune response.