Modulation of innate immunity during hepatitis C virus (HCV) infection. HCV alters the innate immune response at multiple sites. In response to HCV infection, (1) natural killer (NK) cells elaborate interferon-γ to mediate antiviral effects. However, (2) HCV E2 protein binds the NK CD81 receptor, decreasing release of interferon-γ and cytotoxic granules by NK cells. (3) HCV core protein increases major histocompatibility complex class I expression on infected hepatocytes, decreasing NK cell activity against infected cells. (4) Protection from, and clearance of, HCV infection have been associated with a KIR2L3 and HLA-C1 receptor-ligand pairing. (5) Dendritic cells release cytokines IL-12 and IL-15, which augment NK cell function and survival. However, HCV depresses dendritic cell function and number. (6) HCV increases the regulatory T cell population in the liver. Regulatory T cells secrete transforming growth factor–β and IL-10 to decrease NK cell function. (7) HCV proteins ablate signaling pathways in the infected cell to block intracellular pathways associated with innate immunity. In the infected cell, the nonstructural proteins of HCV, notably NS3/4a protein, interact with various host adaptor molecules to block type I interferon induction pathways and the antiviral effects of interferon. Plus sign, activating; minus sign, inhibiting.