{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:34:36Z","timestamp":1791326076613,"version":"4.3.1"},"reference-count":60,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,3,23]],"date-time":"2017-03-23T00:00:00Z","timestamp":1490227200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,3,23]],"date-time":"2017-03-23T00:00:00Z","timestamp":1490227200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Interferon alpha (IFN\u03b1) is commonly used for the treatment of chronic hepatitis B (CHB) patients. There are 13 different IFN\u03b1 subtypes in humans, but only the subtype IFN\u03b12 is used for clinical treatment. The antiviral activities of all other IFN\u03b1 subtypes against HBV have not been studied. To obtain basic knowledge about the direct antiviral as well as the immunomodulatory effects of IFN\u03b1 subtypes, we used the HBV hydrodynamic injection (HI) mouse model. Application of most IFN\u03b1 subtype proteins inhibited HBV replication <jats:italic>in vivo<\/jats:italic>, with IFN\u03b14 and IFN\u03b15 being the most effective subtypes. Decreased viral loads after therapeutic application of IFN\u03b14 and IFN\u03b15 correlated with expanded effector cell populations of NK cells and T cells in both liver and spleen. Hydrodynamic injection of plasmids encoding for the effective IFN\u03b1 subtypes (pIFN\u03b1) was even more potent against HBV than injecting IFN\u03b1 proteins. The combination of pIFN\u03b14 and pIFN\u03b15 showed a synergistic antiviral effect on HBV replication, with a strong increase in NK cell and T cell activity. The results demonstrate distinct anti-HBV effects of different IFN\u03b1 subtypes against HBV in the mouse model, which may be relevant for new therapeutic approaches.<\/jats:p>","DOI":"10.1038\/s41598-017-00469-1","type":"journal-article","created":{"date-parts":[[2017,3,17]],"date-time":"2017-03-17T14:13:04Z","timestamp":1489759984000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Different antiviral effects of IFN\u03b1 subtypes in a mouse model of HBV infection"],"prefix":"10.1038","volume":"7","author":[{"given":"Jingjiao","family":"Song","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Francois","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengji","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongliang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulf","family":"Dittmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Sutter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,3,23]]},"reference":[{"key":"469_CR1","doi-asserted-by":"publisher","first-page":"2212","DOI":"10.1016\/j.vaccine.2011.12.116","volume":"30","author":"JJ Ott","year":"2012","unstructured":"Ott, J. J., Stevens, G. A., Groeger, J. & Wiersma, S. T. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine \n                           30, 2212\u20132219, doi:10.1016\/j.vaccine.2011.12.116 (2012).","journal-title":"Vaccine"},{"key":"469_CR2","doi-asserted-by":"publisher","first-page":"3764","DOI":"10.1073\/pnas.91.9.3764","volume":"91","author":"LG Guidotti","year":"1994","unstructured":"Guidotti, L. G. et al. Cytotoxic T lymphocytes inhibit hepatitis B virus gene expression by a noncytolytic mechanism in transgenic mice. Proc Natl Acad Sci USA \n                           91, 3764\u20133768 (1994).","journal-title":"Proc Natl Acad Sci USA"},{"key":"469_CR3","doi-asserted-by":"publisher","first-page":"9652","DOI":"10.1128\/JVI.00867-09","volume":"83","author":"S Asabe","year":"2009","unstructured":"Asabe, S. et al. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J Virol \n                           83, 9652\u20139662, doi:10.1128\/JVI.00867-09 (2009).","journal-title":"J Virol"},{"key":"469_CR4","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.1016\/S0016-5085(99)70289-1","volume":"117","author":"MK Maini","year":"1999","unstructured":"Maini, M. K. et al. Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection. Gastroenterology \n                           117, 1386\u20131396 (1999).","journal-title":"Gastroenterology"},{"key":"469_CR5","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1128\/JVI.77.1.68-76.2003","volume":"77","author":"R Thimme","year":"2003","unstructured":"Thimme, R. et al. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol \n                           77, 68\u201376 (2003).","journal-title":"J Virol"},{"key":"469_CR6","doi-asserted-by":"publisher","first-page":"5707","DOI":"10.1128\/JVI.78.11.5707-5719.2004","volume":"78","author":"GJ Webster","year":"2004","unstructured":"Webster, G. J. et al. Longitudinal analysis of CD8+ T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B: implications for immunotherapy. Journal of virology \n                           78, 5707\u20135719, doi:10.1128\/JVI.78.11.5707-5719.2004 (2004).","journal-title":"Journal of virology"},{"key":"469_CR7","doi-asserted-by":"publisher","first-page":"1835","DOI":"10.1172\/JCI33402","volume":"118","author":"AR Lopes","year":"2008","unstructured":"Lopes, A. R. et al. Bim-mediated deletion of antigen-specific CD8 T cells in patients unable to control HBV infection. The Journal of clinical investigation \n                           118, 1835\u20131845, doi:10.1172\/JCI33402 (2008).","journal-title":"The Journal of clinical investigation"},{"key":"469_CR8","doi-asserted-by":"publisher","first-page":"537","DOI":"10.3748\/wjg.v7.i4.537","volume":"7","author":"FS Wang","year":"2001","unstructured":"Wang, F. S. et al. Dysfunction of peripheral blood dendritic cells from patients with chronic hepatitis B virus infection. World journal of gastroenterology \n                           7, 537\u2013541 (2001).","journal-title":"World journal of gastroenterology"},{"key":"469_CR9","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1002\/hep.20366","volume":"40","author":"RG van der Molen","year":"2004","unstructured":"van der Molen, R. G. et al. Functional impairment of myeloid and plasmacytoid dendritic cells of patients with chronic hepatitis B. Hepatology \n                           40, 738\u2013746, doi:10.1002\/hep.20366 (2004).","journal-title":"Hepatology"},{"key":"469_CR10","doi-asserted-by":"publisher","first-page":"4215","DOI":"10.1128\/JVI.02844-06","volume":"81","author":"C Boni","year":"2007","unstructured":"Boni, C. et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. Journal of virology \n                           81, 4215\u20134225, doi:10.1128\/JVI.02844-06 (2007).","journal-title":"Journal of virology"},{"key":"469_CR11","doi-asserted-by":"publisher","first-page":"1494","DOI":"10.1002\/hep.24249","volume":"53","author":"A Schurich","year":"2011","unstructured":"Schurich, A. et al. Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in persistent hepatitis B virus infection. Hepatology \n                           53, 1494\u20131503, doi:10.1002\/hep.24249 (2011).","journal-title":"Hepatology"},{"key":"469_CR12","doi-asserted-by":"publisher","first-page":"e47648","DOI":"10.1371\/journal.pone.0047648","volume":"7","author":"G Nebbia","year":"2012","unstructured":"Nebbia, G. et al. Upregulation of the Tim-3\/galectin-9 pathway of T cell exhaustion in chronic hepatitis B virus infection. PloS one \n                           7, e47648, doi:10.1371\/journal.pone.0047648 (2012).","journal-title":"PloS one"},{"key":"469_CR13","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1034\/j.1600-0528.2002.017416.x","volume":"174","author":"DG Doherty","year":"2000","unstructured":"Doherty, D. G. & O\u2019Farrelly, C. Innate and adaptive lymphoid cells in the human liver. Immunol Rev \n                           174, 5\u201320 (2000).","journal-title":"Immunol Rev"},{"key":"469_CR14","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1046\/j.1440-1711.2002.01063.x","volume":"80","author":"IR Mackay","year":"2002","unstructured":"Mackay, I. R. Hepatoimmunology: a perspective. Immunology and cell biology \n                           80, 36\u201344, doi:10.1046\/j.1440-1711.2002.01063.x (2002).","journal-title":"Immunology and cell biology"},{"key":"469_CR15","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1136\/gut.2008.163600","volume":"58","author":"P Fisicaro","year":"2009","unstructured":"Fisicaro, P. et al. Early kinetics of innate and adaptive immune responses during hepatitis B virus infection. Gut \n                           58, 974\u2013982, doi:10.1136\/gut.2008.163600 (2009).","journal-title":"Gut"},{"key":"469_CR16","doi-asserted-by":"publisher","unstructured":"Zhao, J. J. et al. Natural Killer Cells Are Characterized by the Concomitantly Increased Interferon-gamma and Cytotoxicity in Acute Resolved Hepatitis B Patients. Plos One \n                           7, doi:10.1371\/journal.pone.0049135 (2012).","DOI":"10.1371\/journal.pone.0049135"},{"key":"469_CR17","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1053\/j.gastro.2009.06.054","volume":"137","author":"C Dunn","year":"2009","unstructured":"Dunn, C. et al. Temporal Analysis of Early Immune Responses in Patients With Acute Hepatitis B Virus Infection. Gastroenterology \n                           137, 1289\u20131300, doi:10.1053\/j.gastro.2009.06.054 (2009).","journal-title":"Gastroenterology"},{"key":"469_CR18","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s00430-008-0101-6","volume":"198","author":"KF Tang","year":"2009","unstructured":"Tang, K. F. et al. Inhibition of hepatitis B virus replication by small interference RNA induces expression of MICA in HepG2.2.15 cells. Medical microbiology and immunology \n                           198, 27\u201332, doi:10.1007\/s00430-008-0101-6 (2009).","journal-title":"Medical microbiology and immunology"},{"key":"469_CR19","doi-asserted-by":"publisher","unstructured":"Peppa, D. et al. Blockade of Immunosuppressive Cytokines Restores NK Cell Antiviral Function in Chronic Hepatitis B Virus Infection. PLoS Pathog \n                           6, doi:10.1371\/journal.ppat.1001227 (2010).","DOI":"10.1371\/journal.ppat.1001227"},{"key":"469_CR20","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1038\/icb.2012.15","volume":"90","author":"PJ Hertzog","year":"2012","unstructured":"Hertzog, P. J. Overview. Type I interferons as primers, activators and inhibitors of innate and adaptive immune responses. Immunol Cell Biol \n                           90, 471\u2013473, doi:10.1038\/icb.2012.15 (2012).","journal-title":"Immunol Cell Biol"},{"key":"469_CR21","doi-asserted-by":"publisher","first-page":"312","DOI":"10.7326\/0003-4819-119-4-199308150-00011","volume":"119","author":"DK Wong","year":"1993","unstructured":"Wong, D. K. et al. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann Intern Med \n                           119, 312\u2013323 (1993).","journal-title":"Ann Intern Med"},{"key":"469_CR22","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.1056\/NEJM199605303342202","volume":"334","author":"C Niederau","year":"1996","unstructured":"Niederau, C. et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med \n                           334, 1422\u20131427, doi:10.1056\/NEJM199605303342202 (1996).","journal-title":"N Engl J Med"},{"key":"469_CR23","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1002\/rmv.554","volume":"18","author":"G Ferir","year":"2008","unstructured":"Ferir, G., Kaptein, S., Neyts, J. & De Clercq, E. Antiviral treatment of chronic hepatitis B virus infections: the past, the present and the future. Rev Med Virol \n                           18, 19\u201334, doi:10.1002\/rmv.554 (2008).","journal-title":"Rev Med Virol"},{"key":"469_CR24","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/j.ygeno.2004.03.003","volume":"84","author":"MP Hardy","year":"2004","unstructured":"Hardy, M. P., Owczarek, C. M., Jermiin, L. S., Ejdeback, M. & Hertzog, P. J. Characterization of the type I interferon locus and identification of novel genes. Genomics \n                           84, 331\u2013345, doi:10.1016\/j.ygeno.2004.03.003 (2004).","journal-title":"Genomics"},{"key":"469_CR25","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/j.cyto.2011.07.019","volume":"56","author":"TB Lavoie","year":"2011","unstructured":"Lavoie, T. B. et al. Binding and activity of all human alpha interferon subtypes. Cytokine \n                           56, 282\u2013289, doi:10.1016\/j.cyto.2011.07.019 (2011).","journal-title":"Cytokine"},{"key":"469_CR26","doi-asserted-by":"publisher","first-page":"2727","DOI":"10.1182\/blood-2002-05-1521","volume":"101","author":"VS Cull","year":"2003","unstructured":"Cull, V. S., Tilbrook, P. A., Bartlett, E. J., Brekalo, N. L. & James, C. M. Type I interferon differential therapy for erythroleukemia: specificity of STAT activation. Blood \n                           101, 2727\u20132735 (2003).","journal-title":"Blood"},{"key":"469_CR27","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.cyto.2010.09.006","volume":"53","author":"HP Moll","year":"2011","unstructured":"Moll, H. P., Maier, T., Zommer, A., Lavoie, T. & Brostjan, C. The differential activity of interferon-alpha subtypes is consistent among distinct target genes and cell types. Cytokine \n                           53, 52\u201359, doi:10.1016\/j.cyto.2010.09.006 (2011).","journal-title":"Cytokine"},{"key":"469_CR28","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.virol.2009.10.013","volume":"396","author":"L Li","year":"2010","unstructured":"Li, L. & Sherry, B. IFN-alpha expression and antiviral effects are subtype and cell type specific in the cardiac response to viral infection. Virology \n                           396, 59\u201368, doi:10.1016\/j.virol.2009.10.013 (2010).","journal-title":"Virology"},{"key":"469_CR29","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/S1386-6346(02)00020-7","volume":"24","author":"S Yamamoto","year":"2002","unstructured":"Yamamoto, S. et al. Different antiviral activities of IFN-alpha subtypes in human liver cell lines: synergism between IFN-alpha2 and IFN-alpha8. Hepatol Res \n                           24, 99 (2002).","journal-title":"Hepatol Res"},{"key":"469_CR30","doi-asserted-by":"publisher","first-page":"e90977","DOI":"10.1371\/journal.pone.0090977","volume":"9","author":"J Song","year":"2014","unstructured":"Song, J. et al. Susceptibility of different hepatitis B virus isolates to interferon-alpha in a mouse model based on hydrodynamic injection. PloS one \n                           9, e90977, doi:10.1371\/journal.pone.0090977 (2014).","journal-title":"PloS one"},{"key":"469_CR31","doi-asserted-by":"publisher","first-page":"6558","DOI":"10.1128\/JVI.76.13.6558-6567.2002","volume":"76","author":"P Harle","year":"2002","unstructured":"Harle, P. et al. Differential effect of murine alpha\/beta interferon transgenes on antagonization of herpes simplex virus type 1 replication. J Virol \n                           76, 6558\u20136567 (2002).","journal-title":"J Virol"},{"key":"469_CR32","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1046\/j.1365-2567.2002.01423.x","volume":"106","author":"VS Cull","year":"2002","unstructured":"Cull, V. S., Bartlett, E. J. & James, C. M. Type I interferon gene therapy protects against cytomegalovirus-induced myocarditis. Immunology \n                           106, 428\u2013437 (2002).","journal-title":"Immunology"},{"key":"469_CR33","doi-asserted-by":"publisher","first-page":"e1002868","DOI":"10.1371\/journal.ppat.1002868","volume":"8","author":"K Gibbert","year":"2012","unstructured":"Gibbert, K. et al. Interferon-alpha Subtype 11 Activates NK Cells and Enables Control of Retroviral Infection. PLoS pathogens \n                           8, e1002868, doi:10.1371\/journal.ppat.1002868 (2012).","journal-title":"PLoS pathogens"},{"key":"469_CR34","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1002\/eji.200838311","volume":"39","author":"N Gerlach","year":"2009","unstructured":"Gerlach, N. et al. Anti-retroviral effects of type I IFN subtypes in vivo. Eur J Immunol \n                           39, 136\u2013146 (2009).","journal-title":"Eur J Immunol"},{"key":"469_CR35","doi-asserted-by":"publisher","unstructured":"Lavender, K. J. et al. Interferon alpha Subtype-specific Suppression of HIV-1 Infection in vivo. Journal of virology, doi:10.1128\/JVI.00451-16 (2016).","DOI":"10.1128\/JVI.00451-16"},{"key":"469_CR36","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1002\/hep.22751","volume":"49","author":"J Wu","year":"2009","unstructured":"Wu, J. et al. Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells. Hepatology \n                           49, 1132\u20131140, doi:10.1002\/hep.22751 (2009).","journal-title":"Hepatology"},{"key":"469_CR37","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1038\/nri2314","volume":"8","author":"AJ Sadler","year":"2008","unstructured":"Sadler, A. J. & Williams, B. R. Interferon-inducible antiviral effectors. Nat Rev Immunol \n                           8, 559\u2013568, doi:10.1038\/nri2314 (2008).","journal-title":"Nat Rev Immunol"},{"key":"469_CR38","doi-asserted-by":"publisher","first-page":"7852","DOI":"10.1074\/jbc.C109.095703","volume":"285","author":"H Sridharan","year":"2010","unstructured":"Sridharan, H., Zhao, C. & Krug, R. M. Species specificity of the NS1 protein of influenza B virus: NS1 binds only human and non-human primate ubiquitin-like ISG15 proteins. J Biol Chem \n                           285, 7852\u20137856, doi:10.1074\/jbc.C109.095703 (2010).","journal-title":"J Biol Chem"},{"key":"469_CR39","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1136\/gut.2009.195545","volume":"59","author":"R Broering","year":"2010","unstructured":"Broering, R. et al. The interferon stimulated gene 15 functions as a proviral factor for the hepatitis C virus and as a regulator of the IFN response. Gut \n                           59, 1111\u20131119, doi:10.1136\/gut.2009.195545 (2010).","journal-title":"Gut"},{"key":"469_CR40","doi-asserted-by":"publisher","first-page":"24865","DOI":"10.1038\/srep24865","volume":"6","author":"CI Real","year":"2016","unstructured":"Real, C. I. et al. Hepatitis B virus genome replication triggers toll-like receptor 3-dependent interferon responses in the absence of hepatitis B surface antigen. Scientific reports \n                           6, 24865, doi:10.1038\/srep24865 (2016).","journal-title":"Scientific reports"},{"key":"469_CR41","doi-asserted-by":"publisher","unstructured":"Lutgehetmann, M. et al. Hepatitis B virus limits response of human hepatocytes to interferon-alpha in chimeric mice. Gastroenterology \n                           140, 2074-2083, 2083 e2071\u20132072, doi:10.1053\/j.gastro.2011.02.057 (2011).","DOI":"10.1053\/j.gastro.2011.02.057"},{"key":"469_CR42","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1073\/pnas.0913498107","volume":"107","author":"PL Yang","year":"2010","unstructured":"Yang, P. L. et al. Immune effectors required for hepatitis B virus clearance. Proc Natl Acad Sci USA \n                           107, 798\u2013802, doi:10.1073\/pnas.0913498107 (2010).","journal-title":"Proc Natl Acad Sci USA"},{"key":"469_CR43","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/hep.23977","volume":"53","author":"Z Zhang","year":"2011","unstructured":"Zhang, Z. et al. Hypercytolytic activity of hepatic natural killer cells correlates with liver injury in chronic hepatitis B patients. Hepatology \n                           53, 73\u201385, doi:10.1002\/hep.23977 (2011).","journal-title":"Hepatology"},{"key":"469_CR44","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1053\/j.gastro.2009.05.047","volume":"137","author":"B Oliviero","year":"2009","unstructured":"Oliviero, B. et al. Natural Killer Cell Functional Dichotomy in Chronic Hepatitis B and Chronic Hepatitis C Virus Infections. Gastroenterology \n                           137, 1151\u20131160, doi:10.1053\/j.gastro.2009.05.047 (2009).","journal-title":"Gastroenterology"},{"key":"469_CR45","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1111\/cei.12470","volume":"179","author":"IL Heiberg","year":"2015","unstructured":"Heiberg, I. L. et al. Defective natural killer cell anti-viral capacity in paediatric HBV infection. Clin Exp Immunol \n                           179, 466\u2013476, doi:10.1111\/cei.12470 (2015).","journal-title":"Clin Exp Immunol"},{"key":"469_CR46","doi-asserted-by":"publisher","first-page":"1755","DOI":"10.1084\/jem.194.12.1755","volume":"194","author":"K Kakimi","year":"2001","unstructured":"Kakimi, K. et al. Blocking chemokine responsive to gamma-2\/interferon (IFN)-gamma inducible protein and monokine induced by IFN-gamma activity in vivo reduces the pathogenetic but not the antiviral potential of hepatitis B virus-specific cytotoxic T lymphocytes. J Exp Med \n                           194, 1755\u20131766 (2001).","journal-title":"J Exp Med"},{"key":"469_CR47","doi-asserted-by":"publisher","first-page":"e1001227","DOI":"10.1371\/journal.ppat.1001227","volume":"6","author":"D Peppa","year":"2010","unstructured":"Peppa, D. et al. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection. PLoS Pathog \n                           6, e1001227, doi:10.1371\/journal.ppat.1001227 (2010).","journal-title":"PLoS Pathog"},{"key":"469_CR48","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.jhep.2010.07.009","volume":"54","author":"ET Tjwa","year":"2011","unstructured":"Tjwa, E. T., van Oord, G. W., Hegmans, J. P., Janssen, H. L. & Woltman, A. M. Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B. J Hepatol \n                           54, 209\u2013218, doi:10.1016\/j.jhep.2010.07.009 (2011).","journal-title":"J Hepatol"},{"key":"469_CR49","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/j.jhep.2012.09.029","volume":"58","author":"L Micco","year":"2013","unstructured":"Micco, L. et al. Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B. J Hepatol \n                           58, 225\u2013233, doi:10.1016\/j.jhep.2012.09.029 (2013).","journal-title":"J Hepatol"},{"key":"469_CR50","doi-asserted-by":"publisher","first-page":"e1003856","DOI":"10.1371\/journal.ppat.1003856","volume":"10","author":"J Liu","year":"2014","unstructured":"Liu, J. et al. Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and PD-L1 blockade in chronic hepadnaviral infection. PLoS Pathog \n                           10, e1003856, doi:10.1371\/journal.ppat.1003856 (2014).","journal-title":"PLoS Pathog"},{"key":"469_CR51","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1007\/s12250-014-3410-5","volume":"29","author":"J Liu","year":"2014","unstructured":"Liu, J., Kosinska, A., Lu, M. & Roggendorf, M. New therapeutic vaccination strategies for the treatment of chronic hepatitis B. Virol Sin \n                           29, 10\u201316, doi:10.1007\/s12250-014-3410-5 (2014).","journal-title":"Virol Sin"},{"key":"469_CR52","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1038\/ni1241","volume":"6","author":"P Klenerman","year":"2005","unstructured":"Klenerman, P. & Hill, A. T cells and viral persistence: lessons from diverse infections. Nat Immunol \n                           6, 873\u2013879 (2005).","journal-title":"Nat Immunol"},{"key":"469_CR53","doi-asserted-by":"publisher","first-page":"e0151717","DOI":"10.1371\/journal.pone.0151717","volume":"11","author":"KK Dietze","year":"2016","unstructured":"Dietze, K. K. et al. Characterization of the Treg Response in the Hepatitis B Virus Hydrodynamic Injection Mouse Model. PLoS One \n                           11, e0151717, doi:10.1371\/journal.pone.0151717 (2016).","journal-title":"PLoS One"},{"key":"469_CR54","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1111\/jvh.12189","volume":"21","author":"MF Sprinzl","year":"2014","unstructured":"Sprinzl, M. F. et al. Hepatitis B virus-specific T-cell responses during IFN administration in a small cohort of chronic hepatitis B patients under nucleos(t)ide analogue treatment. J Viral Hepat \n                           21, 633\u2013641, doi:10.1111\/jvh.12189 (2014).","journal-title":"J Viral Hepat"},{"key":"469_CR55","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.jhep.2013.08.020","volume":"60","author":"AT Tan","year":"2014","unstructured":"Tan, A. T. et al. Reduction of HBV replication prolongs the early immunological response to IFNalpha therapy. J Hepatol \n                           60, 54\u201361, doi:10.1016\/j.jhep.2013.08.020 (2014).","journal-title":"J Hepatol"},{"key":"469_CR56","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1016\/j.jhep.2011.12.032","volume":"56","author":"A Penna","year":"2012","unstructured":"Penna, A. et al. Peginterferon-alpha does not improve early peripheral blood HBV-specific T-cell responses in HBeAg-negative chronic hepatitis. J Hepatol \n                           56, 1239\u20131246, doi:10.1016\/j.jhep.2011.12.032 (2012).","journal-title":"J Hepatol"},{"key":"469_CR57","doi-asserted-by":"publisher","first-page":"1369","DOI":"10.1038\/sj.gt.3301809","volume":"9","author":"VS Cull","year":"2002","unstructured":"Cull, V. S., Broomfield, S., Bartlett, E. J., Brekalo, N. L. & James, C. M. Coimmunisation with type I IFN genes enhances protective immunity against cytomegalovirus and myocarditis in gB DNA-vaccinated mice. Gene Ther \n                           9, 1369\u20131378 (2002).","journal-title":"Gene Ther"},{"key":"469_CR58","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.jim.2005.08.005","volume":"306","author":"M Bollati-Fogolin","year":"2005","unstructured":"Bollati-Fogolin, M. & Muller, W. Virus free, cell-based assay for the quantification of murine type I interferons. J Immunol Methods \n                           306, 169\u2013175 (2005).","journal-title":"J Immunol Methods"},{"key":"469_CR59","doi-asserted-by":"publisher","first-page":"17862","DOI":"10.1073\/pnas.0608578103","volume":"103","author":"LR Huang","year":"2006","unstructured":"Huang, L. R., Wu, H. L., Chen, P. J. & Chen, D. S. An immunocompetent mouse model for the tolerance of human chronic hepatitis B virus infection. Proc Natl Acad Sci USA \n                           103, 17862\u201317867, doi:10.1073\/pnas.0608578103 (2006).","journal-title":"Proc Natl Acad Sci USA"},{"key":"469_CR60","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.1084\/jem.160.5.1431","volume":"160","author":"RH Wiltrout","year":"1984","unstructured":"Wiltrout, R. H. et al. Augmentation of organ-associated natural killer activity by biological response modifiers. Isolation and characterization of large granular lymphocytes from the liver. J Exp Med \n                           160, 1431\u20131449 (1984).","journal-title":"J Exp Med"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00469-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00469-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00469-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T03:13:22Z","timestamp":1671765202000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00469-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,23]]},"references-count":60,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["469"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-00469-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,23]]},"assertion":[{"value":"4 August 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 February 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 March 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"334"}}