Figure 7. Multiple levels of control of IFN induction during HCV infection.

Soon after infection, the HCV RNA is detected by the dsRNA binding domains (DRBD) of PKR ahead (2 hr) of its recognition by the RNA helicase RIG-I (6 hr). Recruitment of PKR by HCV triggers a signaling pathway that involves PKR as an adapter protein to recruit MAVS and TRAF3. This leads to a strong induction of the di-ubiquitine like protein ISG15 as well as other IRF3-dependent ISGs (Interferon-Stimulated Genes). ISG15 negatively controls the TRIM25-mediated ubiquitination (Ub) of RIG-I through an ISGylation process and thus interferes with the ability of RIG-I to recruit its downstream partners, including MAVS and TRAF3, and to induce IFNβ and ISGs. As the infection proceeds, HCV activates the eIF2α kinase function of PKR (12 hr). This leads to a transient (few hours) inhibition of general translation, including that of IFN [8] and ISGs [9] while the eIF2α-independent translation of the viral proteins proceeds unabated. At later times in the infection (18 hr), additional control of IFN induction occurs through cleavage of MAVS by the HCV NS3/4A protease, once the viral proteins have sufficiently accumulated in the cytosol [7], [27].