HLA CLASS I-RESTRICTED CYTOTOXIC T-LYMPHOCYTES SPECIFIC FOR HEPATITIS-C VIRUS - IDENTIFICATION OF MULTIPLE EPITOPES AND CHARACTERIZATION OFPATTERNS OF CYTOKINE RELEASE

Cytotoxic T lymphocytes (CTL) are important to the control of viral re plication and their presence may be important to disease outcome, An u nderstanding of the spectrum of proteins recognized by hepatitis C vir us (HCV)-specific CTL and the functional properties of these cells is an important step in understanding the disease process and the mechani sms of persistent infection, which occurs in the majority of HCV-infec ted individuals, In this report we identify HCV-specific CTL responses restricted by the HLA class I molecules A2, A3, A11, A23, B7, B8, and B53, The epitopes recognized by these intrahepatic CTL conform to pub lished motifs for binding to HLA class I molecules, although in some c ases we have identified CTL epitopes for which no published motif exis ts, The use of vectors expressing two different strains of HCV, HCV-1 and HCV-H, revealed both strain-specific and cross-reactive CTL, These HCV-specific CTL were shown to produce cytokines including IFN-gamma, TNF-alpha, GM-CSF, IL-8, and IL-10 in an antigen- and HLA class I-spe cific manner, These studies indicate that the CTL response to HCV is b roadly directed and that as many as five different epitopes may be tar geted in a single individual, The identification of minimal epitopes m ay facilitate peptide-specific immunization strategies, In addition, t he release of proinflammatory cytokines by these cells may contribute to the pathogenesis of HCV-induced liver damage.