Our studies, using the THP1 cell culture model of HCV exposure, reveal that exposure of macrophages to HCV induces IL-1β through a process of infection-independent phagocytic virus uptake that triggers signaling through MyD88/TLR7 and NLRP3 inflammasome pathways to drive IL-1β expression and maturation/secretion, respectively. Here, NLRP3 is linked to infection.