Control of Hepatitis C Virus Replication in Mouse Liver-Derived Cells by MAVS-Dependent Production of Type I and Type III Interferons

Hepatitis C virus (HCV) efficiently infects only humans and chimpanzees. Although the detailed mechanisms responsible for this narrow species tropism remain elusive, recent evidence has shown that murine innate immune responses efficiently sup-press HCV replication. Therefore, poor adaptation of HCV to evade and/or counteract innate immune responses may prevent HCV replication in mice. The HCVNS3-4A protease cleaves humanMAVS, a key cellular adaptor protein required for RIG-I-like receptor (RLR)-dependent innate immune signaling. However, it is unclear if HCV interferes with mouseMAVS function equally well. Moreover, MAVS-dependent signaling events that restrict HCV replication in mouse cells were incompletely de-fined. Thus, we quantified the ability of HCVNS3-4A to counteract mouse and humanMAVS. HCVNS3-4A similarly dimin-ished both human andmouseMAVS-dependent signaling in human andmouse cells. Moreover, replicon-encoded protease cleaved a similar fraction of bothMAVS variants. Finally, FLAG-taggedMAVS proteins repressed HCV replication to similar degrees. Depending onMAVS expression, HCV replication in mouse liver cells triggered not only type I but also type III IFNs, which cooperatively repressed HCV replication. Mouse liver cells lacking both type I and III IFN receptors were refractory to MAVS-dependent antiviral effects, indicating that the HCV-inducedMAVS-dependent antiviral state depends on both type I and III IFN receptor signaling. IMPORTANC