本帖最后由 StephenW 于 2014-1-15 16:11 编辑
Adenoviral Delivery of Recombinant Hepatitis B Virus Expressing Foreign Antigenic Epitopes for Immunotherapy of Persistent Viral Infection - Zhuo Wang1,
- Kai Zhu1,
- Weiya Bai2,
- Baosen Jia1,
- Hao Hu1,
- Dongming Zhou1,
- Xiaoming Zhang1,
- Xinxin Zhang3,
- Youhua Xie2,
- Maryline Mancini-Bourgine4,
- Marie-Louise Michel4,
- Ke Lan1# and
- Qiang Deng1#
- Author Affiliations - 1Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
- 2Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China.
- 3Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- 4Laboratoire de Pathogenèse des Virus de l'Hépatite B, Institut Pasteur/INSERM U 845, Paris, France.
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 (wt) HBV-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 concerned 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 largely 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 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.
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发表于 2014-1-15 11:35
