title: Therapeutic recovery of hepatitis B virus (HBV)-induced hepatocyte-intrinsic immune defect reverses systemic adaptive immune tolerance.
abstract: Hepatitis B virus (HBV) persistence aggravates hepatic immunotolerance, leading to the failure of cell-intrinsic type I interferon and antiviral response, but whether and how HBV-induced hepatocyte-intrinsic tolerance influences systemic adaptive immunity has never been reported, which is becoming the major obstacle for chronic HBV therapy. In this study, an HBV-persistent mouse, established by hydrodynamic injection of an HBV-genome-containing plasmid, exhibited not only hepatocyte-intrinsic but also systemic immunotolerance to HBV rechallenge. HBV-specific CD8(+) T-cell and anti-HBs antibody generation were systemically impaired by HBV persistence in hepatocytes. Interestingly, HBV-induced hepatocyte-intrinsic immune tolerance was reversed when a dually functional vector containing both an immunostimulating single-stranded RNA (ssRNA) and an HBx-silencing short hairpin RNA (shRNA) was administered, and the systemic anti-HBV adaptive immune responses, including CD8(+) T-cell and anti-HBs antibody responses, were efficiently recovered. During this process, CD8(+) T cells and interferon-gamma (IFN-γ) secreted play a critical role in clearance of HBV. However, when IFN-α/β receptor was blocked or the Toll-like receptor (TLR)7 signaling pathway was inhibited, the activation of CD8(+) T cells and clearance of HBV was significantly impaired.
  
  
  CONCLUSIONS
  These results suggest that recovery of HBV-impaired hepatocyte-intrinsic innate immunity by the dually functional vector might overcome systemic adaptive immunotolerance in an IFN-α- and TLR7-dependent manner. The strategy holds promise for therapeutic intervention of chronic persistent virus infection and associated cancers.
authors: Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Shandong, China.
authors: Peixiang
authors: P
authors: Lan
authors: Cai
authors: C
authors: Zhang
authors: Qiuju
authors: Q
authors: Han
authors: Jian
authors: J
authors: Zhang
authors: Zhigang
authors: Z
authors: Tian
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005822:Genetic Vectors / Q000276:immunology; D056945:Hep G2 Cells; D006510:Hepatitis B Antibodies / Q000276:immunology; D006514:Hepatitis B Surface Antigens / Q000097:blood / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology*; D022781:Hepatocytes / Q000821:virology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology; D007370:Interferon Type I / Q000037:antagonists & inhibitors; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics / Q000627:therapeutic use; D051199:Toll-Like Receptor 7 / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D007370:Interferon Type I; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7