title: Adenoviral delivery of recombinant hepatitis B virus expressing foreign antigenic epitopes for immunotherapy of persistent viral infection.
abstract: We previously reported a proof-of-concept study for curing chronic hepatitis B virus (HBV) infection using a foreign-antigen recombinant HBV (rHBV) as a gene therapy vector. Targeted elimination of wild-type HBV (wtHBV)-infected cells could be achieved by functionally activating an in situ T-cell response against the foreign antigen. However, as chronic HBV infection spreads to all hepatocytes, specific targeting of virus-infected cells is thought to be less critical. It is also feared that rHBV may not induce active immunization in a setting resembling natural infection. For this immunotherapeutic approach to be practically viable, in the present study, we used a recombinant adenovirus (rAd) vector for rHBV delivery. The rAd vector allowed efficient transduction of wtHBV-producing HepG2 cells, with transferred rHBV undergoing dominant viral replication. Progeny rHBV virions proved to be infectious, as demonstrated in primary tupaia hepatocytes. These results greatly expanded the antiviral capacity of the replication-defective rAd/rHBV in wtHBV-infected liver tissue. With prior priming in the periphery, transduction with rAd/rHBV attracted a substantial influx of the foreign-antigen-specific T-effector cells into the liver. Despite the fully activated T-cell response, active expression of rHBV was observed for a prolonged time, which is essential for rHBV to achieve sustained expansion. In a mouse model of HBV persistence established by infection with a recombinant adeno-associated virus carrying the wtHBV genome, rAd/rHBV-based immunotherapy elicited a foreign-antigen-specific T-cell response that triggered effective viral clearance and subsequent seroconversion to HBV. It therefore represents an efficient strategy to overcome immune tolerance, thereby eliminating chronic HBV infection.
  
  
  OBJECTIVE
  Adenovirus-delivered rHBV activated a foreign-antigen-specific T-cell response that abrogated HBV persistence in a mouse model. Our study provides further evidence of the potential of foreign-antigen-based immunotherapy for the treatment of chronic HBV infection.
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.forename: Kai
authors.initials: K
authors.lastname: Zhu
authors.forename: Weiya
authors.initials: W
authors.lastname: Bai
authors.forename: Baosen
authors.initials: B
authors.lastname: Jia
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.forename: Dongming
authors.initials: D
authors.lastname: Zhou
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhang
authors.forename: Xinxin
authors.initials: X
authors.lastname: Zhang
authors.forename: Youhua
authors.initials: Y
authors.lastname: Xie
authors.forename: Maryline Mancini
authors.initials: MM
authors.lastname: Bourgine
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Michel
authors.forename: Ke
authors.initials: K
authors.lastname: Lan
authors.forename: Qiang
authors.initials: Q
authors.lastname: Deng
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D061605:Administration, Intravenous; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D000939:Epitopes / Q000235:genetics* / Q000276:immunology; D015870:Gene Expression; D023061:Gene Order; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology; D006801:Humans; D007114:Immunization; D007167:Immunotherapy; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014161:Transduction, Genetic; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology; D014771:Virion / Q000502:physiology; D019065:Virus Assembly; D014779:Virus Replication
chemical_list: D000939:Epitopes; D011993:Recombinant Fusion Proteins; D014758:Viral Core Proteins