重组乙型肝炎病毒表达外国抗原表位的持久性病毒感染的免

StephenW

Adenoviral Delivery of Recombinant Hepatitis B Virus Expressing Foreign Antigenic Epitopes for Immunotherapy of Persistent Viral Infection

    Zhuo Wang a,
    Kai Zhu a,
    Weiya Bai b,
    Baosen Jia a,
    Hao Hu a,
    Dongming Zhou a,
    Xiaoming Zhang a,
    Xinxin Zhang c,
    Youhua Xie b,
    Maryline Mancini Bourgine d,
    Marie-Louise Michel d,
    Ke Lan a and
    Qiang Deng a

    a Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
    b Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China
    c Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    d Laboratoire de Pathogenèse des Virus de l'Hépatite B, Institut Pasteur/INSERM U 845, Paris, France

    R. M. Sandri-Goldin, Editor

- Author Affiliations
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.

IMPORTANCE 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.
FOOTNOTES

        Received 25 September 2013.
        Accepted 19 December 2013.
    Address correspondence to Qiang Deng, [email protected], or Ke Lan, [email protected].

StephenW

重组乙型肝炎病毒表达外国抗原表位的持久性病毒感染的免疫治疗腺病毒转染

    卓旺一个，
    朱凯一，
    维亚白B，
    王宝森佳一，
    胡昊一，
    周东明一，
    张晓明一，
    张欣欣C，
    油花谢B，
    Maryline曼奇尼Bourgine D，
    玛丽 - 路易丝·米歇尔D，
    柯蓝一和
    邓羌一

    分子病毒学与免疫学，上海巴斯德研究所，中国院士，上海，中国的重点实验室
    医学分子病毒学，上海医学院，复旦大学，上海，中国的B键实验室
    传染病丙部门，瑞金医院，上海交通大学医学院，上海，中国的
    ð了Laboratoire德Pathogenèse DES病毒DE L' Hépatite B，巴斯德研究所/ INSERM ü 845 ，巴黎，法国

    R. M.山德里 - 戈尔丁编辑器

- 作者所属机构
摘要

我们以前报道证明了概念的研究用于治疗慢性乙型肝炎病毒（ HBV）感染用的是国外抗原的重组乙型肝炎病毒（ RHBV ）作为基因治疗载体。靶向消除野生型HBV （ wtHBV ）的感染的细胞可以通过在功能激活针对外来抗原的原位T细胞应答来实现。然而，如慢性HBV感染扩散到所有肝细胞，病毒感染细胞的特异性靶向被认为是不那么重要。它也担心， RHBV可能不会诱发主动免疫在类似自然感染的设置。对于本免疫治疗方法是可行的实际，在本研究中，我们使用的RHBV递送重组腺病毒（RAD）向量。 RAD的向量允许wtHBV生产HepG2细胞的高效转导，与转移RHBV进行主导病毒复制。子代病毒粒子RHBV被证明是传染病，主要表现在主树鼩肝细胞。这些结果大大扩展的复制缺陷型rAd / RHBV在wtHBV感染的肝组织的抗病毒能力。与在外围事先吸，传导带弧度/ RHBV吸引外来抗原特异性T效应细胞到肝脏的主要流入。尽管完全激活的T-细胞应答时，观察一段较长的时间，这是必不可少的RHBV实现持续的膨胀RHBV的活性的表达。在感染的重组腺相关病毒携带wtHBV基因组建立持久的HBV的小鼠模型，弧度/ RHBV为基础的免疫疗法引起触发有效的病毒清除和随后的血清转换对HBV外商抗原特异性T细胞反应。因此，它是一种有效的策略，以克服免疫耐受，从而消除慢性HBV感染。

重要性腺病毒传递RHBV激活该废止乙肝病毒的持久性在小鼠模型中外商抗原特异性T细胞反应。我们的研究提供外商抗原为基础的免疫疗法用于治疗慢性HBV感染的治疗潜力的进一步证据。
脚注

        收到2013年9月25日。
        接受2013年12月19日。
    地址对应邓强， [email protected] ，还是柯蓝， [email protected] 。

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