The study investigates the role of cellular microRNAs (miRNAs) in the antiviral response to viral infections in mammalian organisms, specifically focusing on the hepatitis C virus (HCV). The authors demonstrate that interferon beta (IFNβ) rapidly modulates the expression of numerous cellular miRNAs, and eight of these IFNβ-induced miRNAs have sequence-predicted targets within the HCV genomic RNA. Synthetic miRNA-mimics corresponding to these IFNβ-induced miRNAs reproduce the antiviral effects of IFNβ on HCV replication and infection. Neutralization of these antiviral miRNAs with anti-miRNAs reduces the antiviral effects of IFNβ against HCV. Additionally, IFNβ treatment leads to a significant reduction in the expression of the liver-specific miR-122, which is essential for HCV replication. These findings support the notion that mammalian organisms use cellular miRNAs, regulated by the interferon system, to combat viral infections. The study also provides evidence for rapid changes in cellular miRNA levels in response to ligand stimulation, contributing to the understanding of the host defense mechanisms in mammalian cells.The study investigates the role of cellular microRNAs (miRNAs) in the antiviral response to viral infections in mammalian organisms, specifically focusing on the hepatitis C virus (HCV). The authors demonstrate that interferon beta (IFNβ) rapidly modulates the expression of numerous cellular miRNAs, and eight of these IFNβ-induced miRNAs have sequence-predicted targets within the HCV genomic RNA. Synthetic miRNA-mimics corresponding to these IFNβ-induced miRNAs reproduce the antiviral effects of IFNβ on HCV replication and infection. Neutralization of these antiviral miRNAs with anti-miRNAs reduces the antiviral effects of IFNβ against HCV. Additionally, IFNβ treatment leads to a significant reduction in the expression of the liver-specific miR-122, which is essential for HCV replication. These findings support the notion that mammalian organisms use cellular miRNAs, regulated by the interferon system, to combat viral infections. The study also provides evidence for rapid changes in cellular miRNA levels in response to ligand stimulation, contributing to the understanding of the host defense mechanisms in mammalian cells.