It is not clear how hepatitis B virus (HBV) modulates host immunity during chronic infection. In addition to the key mediators of
inflammatory response in viral infection, monocytes also express a high-level IFN-stimulated gene, CH25H, upon response to IFN-a
exerting an antiviral effect. In this study, the mechanism by which HBV manipulates IFN signaling in human monocytes was
investigated. We observed that monocytes from chronic hepatitis B patients express lower levels of IFN signaling/stimulated genes
and higher levels of inflammatory cytokines compared with healthy donors. HBV induces monocyte production of inflammatory
cytokines via TLR2/MyD88/NF-kB signaling and STAT1-Ser727 phosphorylation and inhibits IFN-a–induced stat1, stat2, and
ch25h expression through the inhibition of STAT1-Tyr701 phosphorylation and in an IL-10–dependent, partially autocrine
manner. Further, we found that enhancement of STAT1 activity with a small molecule (2-NP) rescued HBV-mediated inhibition
of IFN signaling and counteracted the induction of inflammatory cytokines. In conclusion, HBV contributes to the monocyte
inflammatory response but inhibits their IFN-a/b responsiveness to impair antiviral innate immunity. These effects are mediated
via differential phosphorylation of Tyr701 and Ser727 of STAT1
