Cells highly permissive to HCV RNA replication have a defective host response. (A) Huh7 and Huh7.5 cells were mock treated (mock), infected with SenV for 20 h (SenV), treated with 10 or 50 U of IFN-α2a/ml for 12 h, or transfected with luc-poly(A) or 5′NTR-luc RNA (HCV) for 8 h. Extracts were subjected to immunoblot analysis for ISG56, SenV, and β-actin abundance. (B) The activity of a transfected IFN-β promoter expression constructs was measured in cells that were mock infected or infected with SenV for 24 h or VSV for 10 h. The results shown are the average firefly luciferase activity ± the SD relative to a Renilla luciferase control. (C) Huh7 and Huh7.5 cells were mock transfected or transfected with 5′NTR-luc, L2198S, or HP HCV replicon RNA. Total cellular RNA was collected at 3, 8, or 12 h, and the level of replicon (HCV), 2′-5′ oligoadenylate synthetase 1 (OAS1), ISG6-16, ISG56, ISG15, and GAPDH RNA as determined by using specific probes. 5′NTR-luc RNA was monitored by using the Luc probe. (D) Huh7 and Huh7.5 cells were mock treated (mock), infected with SenV for 24 h, or transfected with luc-poly(A) (poly A) or HCV 5′NTR-luc RNA (HCV 5′NTR) for 8 h. Cells were processed and stained with anti-IRF3 rabbit serum and a rhodamine-conjugated secondary antibody (panels 1 to 8). Nuclei were visualized by staining with DAPI (panels 9 to 16). Magnification, ×40. The transfection efficiency was monitored by a parallel assessment of luciferase activity; the unit activity values are shown below the corresponding panels. (E) In the left panel, IRF3, ISG56, and actin abundance were evaluated by immunoblot analysis of extracts from untreated Huh7 and Huh7.5 cells or cells treated with 10 U of IFNα-2a/ml for 12 h (IFN) or transfected with HCV 5′NTR-luc RNA for 0, 4, or 8 h. The line at left denotes the position of the high-mass hyperphosphorylated IRF3 isoforms. On the right, proteins were separated on a nondenaturing gel in order to define the abundance of the inactive IRF3 monomer and the active IRF3 dimer complex (indicated at right) in cells that were mock infected or infected with SenV for 20 h.