{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:34:21Z","timestamp":1791326061224,"version":"4.3.1"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2017,11,20]],"date-time":"2017-11-20T00:00:00Z","timestamp":1511136000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2017,11,20]],"date-time":"2017-11-20T00:00:00Z","timestamp":1511136000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:p>\n                    Hepatitis B virus (HBV) infects hepatocytes specifically and causes immune\u2010mediated liver damage. How HBV interacts with the innate immunity at the early phase of infection, either with hepatocytes or other cells in the liver, remains controversial. To address this question, we utilized various human cell\u2010culture models and humanized\n                    <jats:italic toggle=\"yes\">Alb\u2010uPA\/SCID<\/jats:italic>\n                    mice. All these models were unable to mount an interferon (IFN) response despite robust HBV replication. To elucidate the mechanisms involved in the lack of IFN response, we examined whether HBV actively inhibits innate immune functions of hepatocytes. By treating HBV\u2010infected cells with known inducers of the IFN signaling pathway, we observed no alteration of either sensing or downstream IFN response by HBV. We showed that the DNA innate sensing pathways are poorly active in hepatocytes, consistent with muted innate immune recognition of HBV. Upon exposure to high\u2010level HBV, human macrophages could be activated with increased inflammatory cytokine expressions.\n                    <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>\n                    : HBV behaves like a \u201cstealth\u201d virus and is not sensed by, nor actively interferes with, the intrinsic innate immunity of infected hepatocytes. Macrophages are capable of sensing HBV, but require exposure to high HBV titers, potentially explaining the long \u201cwindow period\u201d during acute infection and HBV's propensity to chronic infection. (H\n                    <jats:sc>epatology<\/jats:sc>\n                    2017;66:1779\u20131793)\n                  <\/jats:p>","DOI":"10.1002\/hep.29348","type":"journal-article","created":{"date-parts":[[2017,6,30]],"date-time":"2017-06-30T06:17:14Z","timestamp":1498803434000},"page":"1779-1793","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":167,"title":["Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages"],"prefix":"10.1097","volume":"66","author":[{"given":"Xiaoming","family":"Cheng","sequence":"first","affiliation":[{"name":"Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8460-3893","authenticated-orcid":false,"given":"Yuchen","family":"Xia","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisavet","family":"Serti","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter Daniel","family":"Block","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Chung","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuaki","family":"Chayama","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism,Hiroshima University,Hiroshima,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Rehermann","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. Jake","family":"Liang","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,11,20]]},"reference":[{"key":"hep29348-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1016\/S0140-6736(15)61412-X","article-title":"Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013","volume":"386","year":"2015","journal-title":"Lancet"},{"key":"hep29348-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1016\/S0140-6736(12)61728-0","article-title":"Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010","volume":"380","year":"2012","journal-title":"Lancet"},{"key":"hep29348-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"3719","DOI":"10.1128\/JVI.01844-08","article-title":"Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections","volume":"83","year":"2009","journal-title":"J Virol"},{"key":"hep29348-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1053\/j.gastro.2009.06.054","article-title":"Temporal analysis of early immune responses in patients with acute hepatitis B virus infection","volume":"137","year":"2009","journal-title":"Gastroenterology"},{"key":"hep29348-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"6669","DOI":"10.1073\/pnas.0401771101","article-title":"Genomic analysis of the host response to hepatitis B virus infection","volume":"101","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep29348-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1002\/hep.25730","article-title":"Transcriptomic analysis of the woodchuck model of chronic hepatitis B","volume":"56","year":"2012","journal-title":"Hepatology"},{"key":"hep29348-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"12193","DOI":"10.1073\/pnas.1412631111","article-title":"Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell\u2010derived hepatocellular systems","volume":"111","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep29348-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.immuni.2014.12.016","article-title":"The RNA sensor RIG\u2010I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus","volume":"42","year":"2015","journal-title":"Immunity"},{"key":"hep29348-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"3264","DOI":"10.4049\/jimmunol.1300512","article-title":"Melanoma differentiation\u2010associated gene 5 senses hepatitis B virus and activates innate immune signaling to suppress virus replication","volume":"191","year":"2013","journal-title":"J Immunol"},{"key":"hep29348-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1111\/febs.13563","article-title":"The cyclic GMP\u2010AMP synthetase\u2010STING signaling pathway is required for both the innate immune response against HBV and the suppression of HBV assembly","volume":"283","year":"2016","journal-title":"FEBS J"},{"key":"hep29348-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1128\/JVI.02760-14","article-title":"Hepatitis B virus polymerase disrupts K63\u2010linked ubiquitination of STING to block innate cytosolic DNA\u2010sensing pathways","volume":"89","year":"2015","journal-title":"J Virol"},{"key":"hep29348-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1128\/JVI.01825-10","article-title":"Hepatitis B virus regulatory HBx protein binds to adaptor protein IPS\u20101 and inhibits the activation of beta interferon","volume":"85","year":"2011","journal-title":"J Virol"},{"key":"hep29348-bib-0013-20241017","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1002\/hep.22751","article-title":"Hepatitis B virus suppresses toll\u2010like receptor\u2010mediated innate immune responses in murine parenchymal and nonparenchymal liver cells","volume":"49","year":"2009","journal-title":"Hepatology"},{"key":"hep29348-bib-0014-20241017","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1016\/j.jhep.2015.07.014","article-title":"Early inhibition of hepatocyte innate responses by hepatitis B virus","volume":"63","year":"2015","journal-title":"J Hepatol"},{"key":"hep29348-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"e1005693","DOI":"10.1371\/journal.ppat.1005693","article-title":"Hepatitis B Virus\u2010Induced Parkin\u2010Dependent Recruitment of Linear Ubiquitin Assembly Complex (LUBAC) to Mitochondria and Attenuation of Innate Immunity","volume":"12","year":"2016","journal-title":"PLoS Pathog"},{"key":"hep29348-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1128\/JVI.01292-06","article-title":"Inhibition of alpha interferon signaling by hepatitis B virus","volume":"81","year":"2007","journal-title":"J Virol"},{"key":"hep29348-bib-0017-20241017","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.jhep.2016.10.009","article-title":"Human stem cell\u2010derived hepatocytes as a model for hepatitis B virus infection, spreading and virus\u2010host interactions","volume":"66","year":"2017","journal-title":"J Hepatol"},{"key":"hep29348-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.jhep.2009.09.002","article-title":"Absence of viral interference and different susceptibility to interferon between hepatitis B virus and hepatitis C virus in human hepatocyte chimeric mice","volume":"51","year":"2009","journal-title":"J Hepatol"},{"key":"hep29348-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1053\/j.gastro.2011.12.055","article-title":"HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons","volume":"142","year":"2012","journal-title":"Gastroenterology"},{"key":"hep29348-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1038\/ni.2091","article-title":"The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells","volume":"12","year":"2011","journal-title":"Nat Immunol"},{"key":"hep29348-bib-0021-20241017","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/ni.1876","article-title":"The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a beta\u2010catenin\u2010dependent pathway","volume":"11","year":"2010","journal-title":"Nat Immunol"},{"key":"hep29348-bib-0022-20241017","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1038\/ni.1779","article-title":"RIG\u2010I\u2010dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III\u2010transcribed RNA intermediate","volume":"10","year":"2009","journal-title":"Nat Immunol"},{"key":"hep29348-bib-0023-20241017","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1006\/viro.1999.9983","article-title":"Impaired antiviral response in human hepatoma cells","volume":"263","year":"1999","journal-title":"Virology"},{"key":"hep29348-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"3260","DOI":"10.1099\/vir.0.82959-0","article-title":"Hepatitis B virus polymerase inhibits the interferon\u2010inducible MyD88 promoter by blocking nuclear translocation of Stat1","volume":"88","year":"2007","journal-title":"J Gen Virol"},{"key":"hep29348-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/35099560","article-title":"Recognition of double\u2010stranded RNA and activation of NF\u2010kappaB by Toll\u2010like receptor 3","volume":"413","year":"2001","journal-title":"Nature"},{"key":"hep29348-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nature04734","article-title":"Differential roles of MDA5 and RIG\u2010I helicases in the recognition of RNA viruses","volume":"441","year":"2006","journal-title":"Nature"},{"key":"hep29348-bib-0027-20241017","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1126\/science.1229963","article-title":"Cyclic GMP\u2010AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA","volume":"339","year":"2013","journal-title":"Science"},{"key":"hep29348-bib-0028-20241017","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1038\/ni.1932","article-title":"IFI16 is an innate immune sensor for intracellular DNA","volume":"11","year":"2010","journal-title":"Nat Immunol"},{"key":"hep29348-bib-0029-20241017","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1053\/j.gastro.2015.09.026","article-title":"Interferon\u2010gamma and tumor necrosis factor\u2010alpha produced by T cells reduce the HBV persistence form, cccDNA, without cytolysis","volume":"150","year":"2016","journal-title":"Gastroenterology"},{"key":"hep29348-bib-0030-20241017","first-page":"51","article-title":"Conventional and unconventional mechanisms for capping viral mRNA","volume":"10","year":"2011","journal-title":"Nat Rev Microbiol"},{"key":"hep29348-bib-0031-20241017","doi-asserted-by":"crossref","first-page":"3254","DOI":"10.1128\/jvi.67.6.3254-3263.1993","article-title":"An RNA stem\u2010loop structure directs hepatitis B virus genomic RNA encapsidation","volume":"67","year":"1993","journal-title":"J Virol"},{"key":"hep29348-bib-0032-20241017","doi-asserted-by":"crossref","first-page":"9652","DOI":"10.1128\/JVI.00867-09","article-title":"The size of the viral inoculum contributes to the outcome of hepatitis B virus infection","volume":"83","year":"2009","journal-title":"J Virol"},{"key":"hep29348-bib-0033-20241017","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1097\/00000441-197201000-00005","article-title":"Relationship of virus dose to incubation time of clinical hepatitis and time of appearance of hepatitis\u2010associated antigen","volume":"263","year":"1972","journal-title":"Am J Med Sci"},{"key":"hep29348-bib-0034-20241017","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1002\/hep.21482","article-title":"Regulation of Toll\u2010like receptor\u20102 expression in chronic hepatitis B by the precore protein","volume":"45","year":"2007","journal-title":"Hepatology"},{"key":"hep29348-bib-0035-20241017","first-page":"79","article-title":"The role of TLR2 in infection and immunity","volume":"3","year":"2012","journal-title":"Front Immunol"},{"key":"hep29348-bib-0036-20241017","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1002\/hep.28685","article-title":"Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection","volume":"64","year":"2016","journal-title":"Hepatology"},{"key":"hep29348-bib-0037-20241017","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/nature14156","article-title":"Mitochondrial DNA stress primes the antiviral innate immune response","volume":"520","year":"2015","journal-title":"Nature"},{"key":"hep29348-bib-0038-20241017","doi-asserted-by":"crossref","first-page":"e1004032","DOI":"10.1371\/journal.ppat.1004032","article-title":"Hepatitis B virus infection and immunopathogenesis in a humanized mouse model: induction of human\u2010specific liver fibrosis and M2\u2010like macrophages","volume":"10","year":"2014","journal-title":"PLoS Pathog"},{"key":"hep29348-bib-0039-20241017","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1084\/jem.178.5.1541","article-title":"Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis","volume":"178","year":"1993","journal-title":"J Exp Med"},{"key":"hep29348-bib-0040-20241017","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1002\/hep.23226","article-title":"Not interferon, but interleukin\u20106 controls early gene expression in hepatitis B virus infection","volume":"50","year":"2009","journal-title":"Hepatology"},{"key":"hep29348-bib-0041-20241017","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1093\/infdis\/jiu599","article-title":"Kupffer cells interact with hepatitis B surface antigen in vivo and in vitro, leading to proinflammatory cytokine production and natural killer cell function","volume":"211","year":"2015","journal-title":"J Infect Dis"},{"key":"hep29348-bib-0042-20241017","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1053\/jhep.2003.50310","article-title":"Kinetics of the immune response during HBV and HCV infection","volume":"38","year":"2003","journal-title":"Hepatology"},{"key":"hep29348-bib-0043-20241017","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1038\/nm.2811","article-title":"Hepatitis B virus\u2010induced lipid alterations contribute to natural killer T cell\u2010dependent protective immunity","volume":"18","year":"2012","journal-title":"Nat Med"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.29348","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201712000-00015","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T20:17:54Z","timestamp":1729196274000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201712000-00015"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,20]]},"references-count":43,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2017]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.29348","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11,20]]},"assertion":[{"value":"2017-04-17","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-06-26","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}