A gene delivery vector activating foreign antigenic T cell response

IC

Hepatology. 2009 Nov;50(5):1380-91.

Volume 50 Issue 5, Pages 1380 - 1391
Published Online: 7 Jul 2009

Copyright © 2005 American Association for the Study of Liver Diseases

Hepatitis B virus as a gene delivery vector activating foreign antigenic T cell response that abrogates viral expression in mouse models.

www3.interscience.wiley.com/journal/122501119/abstract

Qiang Deng 1 2 a, Maryline Mancini-Bourgine 1 2, Xiaoming Zhang 3 4, Marie-Christine Cumont 5, Ren Zhu 1 2, Yu-Chun Lone 6, Marie-Louise Michel 1 2 *
1Laboratoire Pathogenèse des Virus de l'Hépatite B, Institut Pasteur, Paris, France
2Institut National de la Santé et de la Recherche Médicale U845, Centre de Recherche Croissance et Signalisation, Faculté de Médecine Paris Descartes, Paris, France
3Unité Régulation Immunitaire et Vaccinologie, Paris, France
4Institut National de la Santé et de la Recherche Médicale U883, Paris, France
5Unité de Recherche et d'Expertise Histotechnologie et Pathologie, Institut Pasteur, Paris, France
6Institut National de la Santé et de la Recherche Médicale U542, Hôpital Paul Brousse, Villejuif, France

email: Marie-Louise Michel ([email protected])

*Correspondence to Marie-Louise Michel, Bâtiment Lwoff, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris Cedex 15

aCurrent address: Unit of Tumor Virus, Institut Pasteur of Shanghai, Shanghai, China

Potential conflict of interest: Nothing to report.
fax: (33)-1-40-61-38-41.

Funded by:
French Consulate in Shanghai
Tsi Jung Memorial Fund
TOTAL fund
Conseil régional d'Ile de France

Abstract
Chronic hepatitis B virus (HBV) infection is characterized by functionally impaired T cell responses. To ensure active immunotherapy, the immune response must be switched from exhausted T cells to functional effectors that can attain the liver and cure the viral infection. We thus designed a recombinant HBV (rHBV) containing a modified viral core gene that specifically delivers a foreign antigenic polyepitope to the liver. This recombinant virus could only be self-maintained in hepatocytes already infected by HBV through capsid complementation. A strong foreign epitope-specific T cell response was first primed in the periphery by way of DNA immunization in human leukocyte antigen (HLA)-A2/DR1 transgenic mice. After the hydrodynamic (hyd.) injection of rHBV, expression of the foreign antigenic polyepitope in hepatocytes attracted/reactivated a vigorous T cell response in situ. Most liver-infiltrating CD8+ T cells proved to be functional effectors. Following DNA priming and hyd. injection, the rHBV-based expression of hepatitis B surface antigen (HBsAg) in mouse liver was almost completely inhibited without causing major liver injury. Studies in HBsAg/HLA-A2/DR1 transgenic mice further validated our approach. Conclusion: For the first time, HBV was used as a gene delivery vector, which strongly triggered functional T cell response and subsequently controlled the viral expression in the liver of surrogate mouse models for HBV infection. It might represent an innovative and promising strategy of active immunotherapy during HBV persistent infection. This concept could even be more generally extended to other chronic viral diseases. (HEPATOLOGY 2009.)
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Received: 8 December 2008; Accepted: 20 June 2009

[ 本帖最后由 IC 于 2009-11-8 20:18 编辑 ]

yangjiuyangba

看不懂！真看不懂！

hatecccdna

我不是学医的，大概解释一下：

实验人员通过基因重组的方法更改了HBV病毒的核心基因，并把这种病毒作为外来抗原引入转基因小鼠的肝脏。这种病毒只能在已经感染HBV的肝细胞内存在。通过静脉注射(?, hydrodynamic injection)能够引起强烈的T细胞反应并在没有明显肝损伤的情况下导致转基因病毒表面抗原的清除。
结论：HBV病毒第一次作为基因传送载体并在转基因小鼠上引起T细胞表达最终达到病毒抑制。这种方法可能作为一种创新的治疗手段用于慢性HBV感染的治疗。