HCV infection and viral replication in hepatocytes triggers activation of antiviral innate and adaptive immune activation. Determinants of the favorable outcome of acute infection and viral elimination, however, are still only partially understood. HCV recognition by pattern recognition receptors including TLRs and helicases is critical for type I IFN production. Coordinated activation of NK cells, DC maturation, and induction of robust HCV-specific Th1-type CD4+ T cell and CD8+ T-cell activation seems to be associated with successful clearance of acute infection. Determinants of chronic infection include low frequency of cytotoxic T lymphocytes directed against few HCV structural and NS proteins and weak CD4+ T-cell proliferative responses. These T-cell defects are associated and possibly related to a defect in functions of both plasmacytoid and myeloid DCs. In addition, the increased proportion of regulatory T cells contributes to the HCV-specific subversion of innate and adaptive immune responses in chronic HCV infection. Increasing evidence suggests that many of these immune defects are related to HCV-induced strategies to undermine immune cell activation. Protease activity of NS3/4A on the different components of pattern recognition receptors and subversion of DC and NK cell functions by HCV proteins create a constantly compromised immune environment. Understanding these new pieces of the puzzle of HCV-induced modulation of host immunity may promise strategies for new, targeted therapeutic approaches.
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