{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:46:19Z","timestamp":1791161179375,"version":"4.1.0"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":942,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,2]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>Treatment with exogenous interferon (IFN)-\u03b1 is not effective in the majority of patients with chronic hepatitis B virus (HBV) infection. Recent evidence suggests that HBV has evolved strategies to block the nuclear translocation of signal transducer and activator of transcription (STAT) 1 to limit IFN-\u03b1\u2013induced cellular antiviral responses. However, it remains unclear whether STAT1 translocation is impaired in chronic hepatitis B patients and what mechanisms are involved. Here we report that the expression of HBV polymerase (Pol) in human hepatic cell lines inhibited induction of IFN-stimulated genes and resulted in a weakened antiviral activity of IFN-\u03b1. Ectopic expression of Pol suppressed IFN-\u03b1\u2013induced STAT1 serine 727 phosphorylation and STAT1\/2 nuclear accumulation, whereas STAT1 tyrosine 701 phosphorylation, and STAT1-STAT2 heterodimer formation were not affected. Further studies demonstrated that Pol interacted with the catalytic domain of protein kinase C-\u03b4 (PKC-\u03b4) and perturbed PKC-\u03b4 phosphorylation and its association with STAT1, which resulted in the suppression of STAT1 Ser727 phosphorylation. Moreover, Pol was found to interfere with nuclear transportation of STAT1\/2 by competitively binding to the region of importin-\u03b15 required for STAT1\/2 recruitment. Truncation analysis suggested that the terminal protein and RNase H domains of Pol were able to bind to PKC-\u03b4 and importin-\u03b15, respectively, and were responsible for the inhibition of IFN-\u03b1 signaling. More importantly, the inhibition of STAT1 and PKC-\u03b4 phosphorylation were confirmed in a hydrodynamic-based HBV mouse model, and the blockage of IFN-\u03b1\u2013induced STAT1\/2 nuclear translocation was observed in HBV-infected cells from liver biopsies of chronic HBV patients.<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n                                 <jats:bold>These results demonstrate a role for Pol in HBV-mediated antagonization of IFN-\u03b1 signaling and provide a possible molecular mechanism by which HBV resists the IFN therapy and maintains its persistence.<\/jats:bold>\n                              <\/jats:p>\n          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