FIGURE 3. HCV attenuates IFN signalling through multiple mechanisms.

Receptor signalling by IFN from autocrine/paracrine and therapeutic sources is subject to feedback inhibition by suppressor of cytokine signalling (SOCS) proteins. The HCV core protein has been shown to induce the aberrant expression of SOCS-3, which can suppress Jak–STAT signalling events and block the IFN-induced formation of ISGF3 (ref. 58). HCV protein expression in liver cells is associated with induction of the protein inhibitor of activated STAT (PIAS) expression and concomitant inhibition of STAT function in vivo, possibly mediated by protein phosphatase 2A (PP2A) signalling events and STAT demethylation⁵⁶. Patients with chronic HCV infection have exhibited high levels of serum IL-8 (ref. 64). The biological activity of IL-8 interferes with IFN signalling events that catalyse ISGF3 assembly and function⁶². HCV modulation of IFN signalling events attenuates ISG expression, allowing HCV to evade the antiviral actions of the host response and IFN therapy.