In conclusion, we have successfully constructed and selected the most effective recombinant lentiviral vector for USP18 shRNA expression in Hepg2.2.15 cells for the first time, which significantly increase the antiviral activity of IFN-α and its influence is associated with the IFN-α signaling pathway, JAK-STAT, indicating that USP18 can be used as a candidate target to explore chronic hepatitis B progression and gene therapy. Here, IFNA2 is linked to chronic hepatitis B virus infection.