Genetic immunization of wild-type and hepatitis C virus transgenic mice reveals a hierarchy of cellular immune response and tolerance induction against hepatitis C virus structural proteins

To study the effect of genetic immunization on transgenic expression of hep atitis C virus (HCV) proteins, we evaluated the immunological response of H CV transgenic mice to HCV expression plasmids. FVB/n transgenic mice expres sing HCV structural proteins (core, E1, and E2) and wild-type (WT) FVB/n mi ce were immunized intramuscularly with plasmids expressing core (pHCVcore) or core/E1/E2 (pHCVSt). After immunization, HCV-specific Immoral and cellul ar immune response was studied. Both WT and transgenic mice immunized with either HCV construct produced antibodies and exhibited T-cell proliferative responses against core or envelope. In WT mice immunized with pHCVSt, cyto toxic T-lymphocyte (CTL) activities were detected against E2 but not agains t core or E1, whereas strong CTL activities against core could be detected in WT mice immunized with pHCVcore. In pHCVSt-immunized, transgenic mice, C TL activities against the core or envelope were completely absent, but core -specific CTL activities could be detected in pHCVcore-immunized transgenic mice. A similar pattern of immune responses was also observed in other mou se strains, including a transgenic line expressing human HLA-A2.1 molecules (AAD mice). Despite the presence of a peripheral cellular immunity against HCV, no liver pathology or lymphocytic infiltrate was observed in these tr ansgenic mice. Our study suggests a hierarchy of CTL response against the H CV structural proteins (E2 > core > E1) in vivo when the proteins are expre ssed as a polyprotein. The HCV transgenic mice can be induced by DNA immuni zation to generate anti-HCV antibodies and anticore CTLs. However, they are tolerant at the CTL level against the E2 protein despite DNA immunization.