Studies conducted predominantly in hepatoma lines have defined RIG-I as the primary PRR required for IFN induction after HCV infection.5 Because V proteins do not engage RIG-I, but do bind helicases MDA5 and LGP2,20, 22 our results may suggest that recognition of HCV RNA occurs differently in primary HFLC cultures, and that infection of these cells leads to the generation of RNA species that are capable of directly activating the MDA5 pathway. Here, RIGI is linked to infection.