Hepatitis C virus (HCV) infection places a heavy burden on health care services worldwide.More than 80% of patients infected with HCV show chronic infection and immunosuppression, which may be due to defects in antigen presentation by myeloid dendritic cells (mDCs).These defects appear to be remedied by treatment with interferon alpha (IFN-a)-based antiviral therapies.However, the molecular mechanisms underlying mDC dysfunction in HCV infection and restoration by IFN-α treatment are unclear.The ubiquitin-editing protein, A20, which negatively modulates NF-κ B signaling, plays a crucial role in controlling the maturation, cytokine production, and immunostimulatory potency of DCs.We thus propose that A20 expression is correlated with the function of mDCs during HCV chronic infection by IFN-α therapy.The present study demonstrated that A20 expression in mDCs isolated from chronically HCV-infected patients was significantly higher than that in healthy subjects or patients achieving SVR (sustained virological response) following treatment.Also, A20 expression in cultured mDCs in response to poly-I:C treatment differed between HCV patients and healthy subjects; this difference was abrogated by treatment with exogenous IFN-α.A20 expression by poly-I:C-activated mDCs (either with or without IFN-α treatment) was negatively correlated with the expression of HLA-DR, CD86 and CCR7, and with the production of IL-12, but positively correlated with the production of IL-10.Silencing A20 expression using small interfering RNAs increased the production of IL-12 production in mDCs of chronically HCV-infected individuals.These findings suggest that A20 plays a crucial role in negative regulation of innate immune responses during chronic viral infection and may be a novel target for immunotherapy to HCV infection.