HLA Class I-restricted Cytotoxic T Lymphocytes Specific for Hepatitis C Virus Identification of Multiple Epitopes and Characterization of Patterns of Cytokine Release

Cytotoxic T lymphocytes (CTL) are important to the con-trol of viral replication and their presence may be important to disease outcome. An understanding of the spectrum of proteins recognized by hepatitis C virus (HCV)-specific CTL and the functional properties of these cells is an im-portant step in understanding the disease process and the mechanisms of persistent infection, which occurs in the ma-jority of HCV-infected individuals. In this report we identify HCV-specific CTL responses restricted by the HLA class I molecules A2, A3, All, A23, B7, B8, and B53. The epitopes recognized by these intrahepatic CTL conform to published motifs for binding to HLA class I molecules, although in some cases we have identified CTL epitopes for which no published motif exists. 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-y, TNF-a, GM-CSF, IL-8, and IL-10 in an antigen- and HLA class I-specific manner. These studies indicate that the CTL response to HCV is broadly directed and that as many as five different epitopes may be targeted in a single individual. The identification of minimal epitopes may facilitate pep-tide-specific immunization strategies. In addition, the re-lease of proinflammatory cytokines by these cells may con-tribute to the pathogenesis of HCV-induced liver damage