TRIM28 Promotes Hepatitis B Virus Replication By Inhibiting The Activation Of JAK/STAT Pathway

Hepatitis B virus(HBV)is a hepadnavirus.With a prevalence of 30%,there are approximately 350 million patients with chronic HBV infection globally.HBV infection can cause chronic hepatitis,cirrhosis,and even liver cancer,and 686,000 individuals died of HBV infection worldwide in 2013.Due to the specificity of HBV infection and the precise regulation of its lifecycle,there is still no effective solution to remove the viral genome.?-interferon(IFN-?),as one of the principle treatments for hepatitis B,can regulate the activation of a large number of antiviral proteins to exert antiviral effects against invasive pathogens.However,the mechanism of IFN-? repressing HBV infection is not broadly understood.Benefited from the co-evolution of virus and host,HBV has evolved a variety of strategies to inhibit innate immune response to establish its persistent infection.Nevertheless,the antiviral activity of IFN against HBV is not ideal enough to remove the viral genome,and side effects are common in clinic.Therefore,better understanding the mechanisms of persistent HBV infection and antiviral mechanism of IFN is of great significance to improve therapeutic effects of IFN-?.TRIM28,a member of TRIM protein family,plays an important role in immune response.In this study,we investigated the relationship between TRIM28 and persistent HBV infection.We found that overexpression of TRIM28 upregulated HBV pgRNA,cccDNA and HBV total DNA levels and attenuated the antiviral effect of IFN-? in human hepatocyte HLCZ01,which supports the infection and replication of HBV.Similarly,TRIM28 knockdown remarkably reduced the replication level of HBV and enhanced the antiviral effect of IFN-? against HBV.Besides,we came to the same conclusion in HepG2.2.15 supporting HBV replication.In deeper study,we demonstrated that TRIM28 inhibited expression of interferon-inducible genes(ISGs)downstream of IFN-JAK-STAT pathway but had no effects on the phosphorylation of STAT1 and STAT2 signaling molecules.Furthermore,we found that the expression level of TRIM28 was significantly higher in the liver tissues of hepatitis B patients than that in non-hepatitis B tissues and HBV infection induced TRIM28 expression in HLCZ01 cells.All the data suggest that HBV may induce the expression of TRIM28 to downregulate ISGs expression in JAK-STAT signaling pathway,and gradually weaken the anti-HBV effect of IFN-? to facilitate replication.Overall,our study provides a new idea for studying the mechanism of chronic HBV infection.