Non-neutralizing epitopes induce robust hepatitis C virus (HCV)-specific antibody-dependent CD56+ natural killer cell responses in chronic HCV-infected patients.

Natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (NK-ADCC) is of considerable interest in viral infection. However, little is known about NK-ADCC responses in chronic hepatitis C virus (HCV) infection. In this study, impaired non-specific antibody-dependent CD56+ NK cell responses were observed in chronic HCV infection, as shown by decreased degranulation (extracellular CD107a expression) and interferon (IFN)-γ production in response to antibody-bound P815 cells. A peptide pool composed of epitopes recognized by anti-HCV-E1/E2 antibodies could induce pronounced HCV-specific antibody-dependent NK cell responses in sera from approximately half the chronic HCV carriers. Additionally, HCV-specific epitopes with the capacity to induce robust NK-ADCC activity were identified. Five linear NK-ADCC epitopes (aa211-aa217, aa384-aa391, aa464-aa475, aa544-aa551 and aa648-aa659 of the HCV envelope) were identified and do not overlap with putative linear neutralizing epitopes. This study revealed the dysfunctional characteristics of antibody-dependent CD56+ NK cell responses in chronic HCV carriers. The key non-neutralizing NK-ADCC epitopes identified in this study may act as new targets for immunological intervention.