Characterization of antigenic variants of hepatitis C virus in immune evasion

Background: Antigenic variation is an effective way by which viruses evade host immune defense leading to viral persistence. Little is known about the inhibitory mechanisms of viral variants on CD4 T cell functions. Results: Using sythetic peptides of a HLA-DRB1*15-restricted CD4 epitope derived from the non-structural (NS) 3 protein of hepatitis C virus (HCV) and its antigenic variants and the peripheral blood mononuclear cells (PBMC) from six HLA-DRB1*15-positive patients chronically infected with HCV and 3 healthy subjects, the in vitro immune responses and the phenotypes of CD4(+)CD25(+) cells of chronic HCV infection were investigated. The variants resulting from single or double amino acid substitutions at the center of the core region of the Th1 peptide not only induce failed T cell activation but also simultaneously up-regulate inhibitory IL-10, CD25(-)TGF-beta(+) Th3 and CD4 (+)IL-10(+) Tr1 cells. In contrast, other variants promote differentiation of CD25(+)TGF-beta(+) Th3 suppressors that attenuate T cell proliferation. Conclusions: Naturally occuring HCV antigenic mutants of a CD4 epitope can shift a protective peripheral Th1 immune response into an inhibitory Th3 and/or Tr1 response. The modulation of antigenic variants on CD4 response is efficient and extensive, and is likely critical in viral persistence in HCV infection.