Wang Zhuo, Zhu Kai, Bai Weiya, Jia Baosen, Hu Hao, Zhou Dongming, Zhang Xiaoming, Zhang Xinxin, Xie Youhua, Bourgine Maryline Mancini, Michel Marie-Louise, Lan Ke, Deng Qiang
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
J Virol. 2014 Mar;88(5):3004-15. doi: 10.1128/JVI.02756-13. Epub 2013 Dec 26.
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.
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.
我们之前报道了一项概念验证研究，该研究使用外源抗原重组乙肝病毒（rHBV）作为基因治疗载体来治愈慢性乙肝病毒（HBV）感染。通过功能激活针对外源抗原的原位T细胞反应，可以实现对野生型HBV（wtHBV）感染细胞的靶向清除。然而，由于慢性HBV感染会扩散到所有肝细胞，因此病毒感染细胞的特异性靶向被认为不那么关键。人们还担心rHBV在类似于自然感染的情况下可能不会诱导主动免疫。为了使这种免疫治疗方法切实可行，在本研究中，我们使用重组腺病毒（rAd）载体来递送rHBV。rAd载体能够高效转导产生wtHBV的HepG2细胞，转入的rHBV会进行优势病毒复制。如在树鼩原代肝细胞中所证实的，子代rHBV病毒粒子具有传染性。这些结果极大地扩展了复制缺陷型rAd/rHBV在wtHBV感染肝组织中的抗病毒能力。在外周预先启动后，用rAd/rHBV进行转导会吸引大量外源抗原特异性T效应细胞流入肝脏。尽管T细胞反应已完全激活，但仍观察到rHBV的活性表达持续了很长时间，这对于rHBV实现持续扩增至关重要。在通过感染携带wtHBV基因组的重组腺相关病毒建立的HBV持续感染小鼠模型中，基于rAd/rHBV的免疫治疗引发了外源抗原特异性T细胞反应，该反应触发了有效的病毒清除以及随后的HBV血清学转换。因此，它代表了一种克服免疫耐受从而消除慢性HBV感染的有效策略。
腺病毒递送的rHBV激活了外源抗原特异性T细胞反应，该反应在小鼠模型中消除了HBV的持续感染。我们的研究进一步证明了基于外源抗原的免疫治疗在治疗慢性HBV感染方面的潜力。
