title: Poly(I:C) treatment leads to interferon-dependent clearance of hepatitis B virus in a hydrodynamic injection mouse model.
abstract: We have previously shown that poly(I:C) activates murine hepatic cells to produce interferon (IFN) and suppresses hepatitis B virus (HBV) replication in vitro. Therefore, we addressed whether poly(I:C) is able to induce the clearance of HBV in vivo. The chronic HBV replication mouse model was established by the hydrodynamic injection (HI) of pAAV-HBV1.2 into the tail veins of wild-type and IFN-α/βR-, IFN-γ-, and CXCR3-deficient C57BL/6 mice. Fourteen days post-HI of pAAV-HBV1.2, mice were administered poly(I:C) by intraperitoneal injection, intramuscular injection, or HI. Only treatment of poly(I:C) by HI led to HBV clearance in wild-type C57BL/6 mice. Serum HBsAg disappeared within 40 days postinfection (dpi) in mice that received poly(I:C) by HI, and this was accompanied by the appearance of anti-HBs antibodies. HBV-specific T-cell and antibody responses were significantly enhanced by HI of poly(I:C). HBV replication intermediates and HBcAg-positive hepatocytes were eliminated in the liver. HI of poly(I:C) induced the production of IFNs in mice and enhanced the levels of cytokines, IFN-stimulated genes, and T-cell markers in the liver. Importantly, poly(I:C)-induced HBV clearance was impaired in IFN-α/βR-, IFN-γ-, and CXCR3-deficient mice, indicating that the induction of type I IFN and the stimulation and recruitment of T cells into the liver are essential for HBV clearance in this model. Taken together, the application of poly(I:C) by HI into the liver enhances innate and adaptive immune responses and leads to HBV clearance in an HBV mouse model, implicating the potential of intrahepatic Toll-like receptor 3 (TLR3) activation for the treatment of chronic hepatitis B patients.
  
  
  OBJECTIVE
  It has become well accepted that immunomodulation is a potentially useful approach to treat chronic viral infection. Recently, combinations of antiviral treatment and therapeutic vaccinations were evaluated for therapies of chronic hepatitis B virus (HBV) infection. Activation of the innate immune branch may also be important for viral control and contributes to HBV clearance. Our present study demonstrated that hepatic TLR3 activation led to clearance of hepatitis B virus in an HBV mouse model. For the first time, we showed that HBV clearance in this model is dependent not only on type I interferon (IFN) but also on type II IFN, indicating a coordinated action of innate and adaptive immune responses. T-cell recruitment appeared to be critical for the success of TLR3-mediated antiviral action. These findings implicate the potential of intrahepatic TLR3 activation for the treatment of chronic HBV infection.
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Shunmei
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Mingfa
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Youchen
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Chan
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xuecheng
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Junzhong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jingjiao
authors.initials: J
authors.lastname: Song
authors.affiliation: Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Ejuan
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Baoju
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Joerg F
authors.initials: JF
authors.lastname: Schlaak
authors.affiliation: Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany Mengji.lu@uni-due.de dlyang@hust.edu.cn.
authors.forename: Mengji
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Mengji.lu@uni-due.de dlyang@hust.edu.cn.
authors.forename: Dongliang
authors.initials: D
authors.lastname: Yang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000821:virology; D022781:Hepatocytes / Q000276:immunology / Q000821:virology; D006801:Humans; D057446:Hydrodynamics; D007372:Interferons / Q000235:genetics / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D007372:Interferons