Deng Qiang, Mancini-Bourgine Maryline, Zhang Xiaoming, Cumont Marie-Christine, Zhu Ren, Lone Yu-Chun, Michel Marie-Louise
Laboratoire Pathogenèse des Virus de l'Hépatite B, Institut Pasteur, Paris, France.
Hepatology. 2009 Nov;50(5):1380-91. doi: 10.1002/hep.23150.
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.
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.
慢性乙型肝炎病毒（HBV）感染的特征是T细胞反应功能受损。为确保主动免疫治疗，免疫反应必须从耗竭的T细胞转变为能够到达肝脏并治愈病毒感染的功能性效应细胞。因此，我们设计了一种重组HBV（rHBV），其包含一个经过修饰的病毒核心基因，该基因可将外源抗原多表位特异性递送至肝脏。这种重组病毒只能通过衣壳互补在已被HBV感染的肝细胞中自我维持。通过在人白细胞抗原（HLA）-A2/DR1转基因小鼠中进行DNA免疫，首先在外周引发强烈的外源表位特异性T细胞反应。在水动力（hyd.）注射rHBV后，肝细胞中外源抗原多表位的表达吸引/激活了原位强烈的T细胞反应。大多数浸润肝脏的CD8(+) T细胞被证明是功能性效应细胞。经过DNA预激发和hyd.注射后，小鼠肝脏中基于rHBV的乙型肝炎表面抗原（HBsAg）表达几乎完全受到抑制，且未引起严重肝损伤。在HBsAg/HLA-A2/DR1转基因小鼠中的研究进一步验证了我们的方法。
首次将HBV用作基因递送载体，其强烈触发功能性T细胞反应，随后在HBV感染的替代小鼠模型肝脏中控制病毒表达。这可能代表了HBV持续感染期间主动免疫治疗的一种创新且有前景的策略。这一概念甚至可更广泛地扩展到其他慢性病毒性疾病。
