{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:00:13Z","timestamp":1791266413745,"version":"4.1.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2012,7,1]],"date-time":"2012-07-01T00:00:00Z","timestamp":1341100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>IFN-\u03b1 is a widely used treatment for hepatitis B virus (HBV) infection, and IFN resistance caused by viral and\/or host factors is currently a challenging clinical problem. A better understanding of the molecular mechanisms underlying IFN immunotherapy in the treatment of viral infection would be very beneficial clinically and is of immense clinical importance. Calreticulin (CRT) is an endoplasmic reticulum luminal calcium-binding chaperone that is involved in the regulation of calcium homoeostasis, the folding of newly synthesized proteins, and many other cellular functions. However, little is known about the role of CRT in HBV infection. In this study, we observed high levels of CRT expression in the sera and PBMCs of patients with HBV relative to those of healthy individuals. HBV upregulated the expression of CRT at the transcriptional level. Further investigation showed that HBV-induced CRT enhanced HBV replication by antagonizing the IFN pathway. CRT suppressed the production of endogenous IFN-\u03b1 by reducing the nuclear translocation of IFN regulatory factor-7 but not IFN regulatory factor-3. Furthermore, CRT also suppressed the antiviral activity of IFN-\u03b1 by inhibiting the phosphorylation of STAT1 and decreasing the expression of two IFN-\u03b1 downstream effectors, protein kinase R and 2\u2032,5\u2032-oligoadenylate synthetase. Our results offer new insights into the pathogenesis of HBV infection and may provide potential targets for anti-HBV therapy.<\/jats:p>","DOI":"10.4049\/jimmunol.1103405","type":"journal-article","created":{"date-parts":[[2012,6,2]],"date-time":"2012-06-02T05:23:17Z","timestamp":1338614597000},"page":"279-286","source":"Crossref","is-referenced-by-count":34,"title":["Hepatitis B Virus-Induced Calreticulin Protein Is Involved in IFN Resistance"],"prefix":"10.1093","volume":"189","author":[{"given":"Xin","family":"Yue","sequence":"first","affiliation":[{"name":"State Key Laboratory of Virology, College of Life Sciences, Wuhan University , Wuhan 430072,","place":["China"]},{"name":"Clinical Research Center, Wuhan Children\u2019s Hospital , Wuhan 430016,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, College of Life Sciences, Wuhan University , Wuhan 430072,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanpeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, College of Life Sciences, Wuhan University , Wuhan 430072,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, College of Life Sciences, Wuhan University , Wuhan 430072,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianguo","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, College of Life Sciences, Wuhan University , Wuhan 430072,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendan","family":"Ren","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, College of Life Sciences, Wuhan University , Wuhan 430072,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, College of Life Sciences, Wuhan University , Wuhan 430072,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,7,1]]},"reference":[{"key":"2025032409161550800_r1","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1136\/bmj.318.7192.1213a","article-title":"More than third of world\u2019s population has been infected with hepatitis B virus","volume":"318","author":"Zuckerman","year":"1999","journal-title":"BMJ"},{"key":"2025032409161550800_r2","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1002\/(SICI)1097-0215(19990315)80:6<827::AID-IJC6>3.0.CO;2-P","article-title":"Estimates of the worldwide incidence of 25 major cancers in 1990","volume":"80","author":"Parkin","year":"1999","journal-title":"Int. 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Interferon Cytokine Res."},{"key":"2025032409161550800_r32","doi-asserted-by":"crossref","first-page":"18601","DOI":"10.1016\/S0021-9258(17)44794-6","article-title":"Differential expression and distinct structure of 69- and 100-kDa forms of 2-5A synthetase in human cells treated with interferon","volume":"265","author":"Mari\u00e9","year":"1990","journal-title":"J. Biol. Chem."},{"key":"2025032409161550800_r33","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1086\/497340","article-title":"Single nucleotide polymorphisms in genes for 2\u2032-5\u2032-oligoadenylate synthetase and RNase L inpatients hospitalized with West Nile virus infection","volume":"192","author":"Yakub","year":"2005","journal-title":"J. Infect. 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Biol."},{"key":"2025032409161550800_r37","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1128\/MCB.18.3.1359","article-title":"Interferon regulatory factor 3 and CREB-binding protein\/p300 are subunits of double-stranded RNA-activated transcription factor DRAF1","volume":"18","author":"Weaver","year":"1998","journal-title":"Mol. Cell. Biol."},{"key":"2025032409161550800_r38","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/S0014-5793(98)01514-2","article-title":"Positive feedback regulation of type I IFN genes by the IFN-inducible transcription factor IRF-7","volume":"441","author":"Sato","year":"1998","journal-title":"FEBS Lett."},{"key":"2025032409161550800_r39","doi-asserted-by":"crossref","first-page":"34320","DOI":"10.1074\/jbc.M002814200","article-title":"Multiple regulatory domains control IRF-7 activity in response to virus infection","volume":"275","author":"Lin","year":"2000","journal-title":"J. Biol. 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