基于IL-21的疗法在小鼠模型中诱导乙型肝炎病毒持续性的清除

StephenW

Theranostics. 2019 May 31;9(13):3798-3811. doi: 10.7150/thno.35331. eCollection 2019.
IL-21-based therapies induce clearance of hepatitis B virus persistence in mouse models.
Shen Z1, Liu J2,3, Wu J1, Zhu Y3, Li G3, Wang J1, Luo M3, Deng Q3, Zhang J1,3, Xie Y3,4.
Author information

1
    Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, People's Republic of China.
2
    Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.
3
    Key Laboratory of Medical Molecular Virology (Ministry of Education/National Health Commission/Chinese Academy of Medical Sciences), Department of Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.
4
    Children's Hospital, Fudan University, Shanghai 201199, People's Republic of China.

Abstract

Chronic hepatitis B virus (HBV) infection causes hepatitis, liver cirrhosis and hepatocellular carcinoma. Covalently closed circular DNA (cccDNA) is the sole viral transcription template and not affected by current treatment options, constituting a key determinant of HBV persistence. Novel therapeutics with demonstrable effectiveness against cccDNA are required. Methods: Previously, we established an HBV persistence mouse model using replicon plasmid derived from a clinical isolate (termed BPS) and identified IL-21 as a potent clearance-inducer. We also described another persistence mouse model based on cccDNA mimics produced in vivo termed recombinant cccDNA (rcccDNA). In this work, effectiveness of IL-21-based gene and cellular therapies was tested using these models. Results: In both models of HBV persistence, single injections with adeno-associated virus (AAV) expressing murine IL-21 highly efficiently induced clearance of both HBV markers from serum, and more importantly, BPS DNA and rcccDNA from mouse liver. Mechanistically, IL-21-induced clearance was associated with activation and liver infiltration of CD8+ T cells, and CD8 antibody injections negatively affected AAV-IL-21 effectiveness. More notably, adoptive transfer of CD8+ T cells from AAV-IL-21-cured mice engendered clearance in acceptor HBV persistence mice. Furthermore, cured mice were protected against re-challenge with long-lived memory. Most significantly, infusion of splenocytes from treatment-naïve mice stimulated ex vivo with IL-21 protein and HBV antigen could also induce clearance in treatment-naïve mice. Conclusion: These data demonstrate IL-21-based gene and cellular therapies as valid candidates for treating chronic HBV infections, with potential in removing cccDNA-harboring hepatocytes via activated CD8+ T cells accompanied by long-term protective memory.
KEYWORDS:

IL-21; cellular immunity; clearance; hepatitis B virus; mouse model

PMID:
    31281514
PMCID:
    PMC6587353
DOI:
    10.7150/thno.35331

StephenW

治疗诊断。 2019年5月31日; 9（13）：3798-3811。 doi：10.7150 / thno.35331。 eCollection 2019。
基于IL-21的疗法在小鼠模型中诱导乙型肝炎病毒持续性的清除。
Shen Z1，Liu J2,3，Wu J1，Zhu Y3，Li G3，Wang J1，Luo M3，Deng Q3，Zhang J1,3，Xie Y3,4。
作者信息

1
    复旦大学附属华山医院感染科，上海200040，中华人民共和国。
2
    复旦大学上海医学院基础医学院生物医学科学研究所医学表观遗传学与代谢重点实验室，上海200032，中华人民共和国。
3
    医学分子病毒学重点实验室（教育部/国家卫生委员会/中国医学科学院），复旦大学上海医学院基础医学院微生物与寄生虫学教研室，上海200032，中华人民共和国。
4
    复旦大学儿童医院，上海201199，中华人民共和国。

抽象

慢性乙型肝炎病毒（HBV）感染引起肝炎，肝硬化和肝细胞癌。共价闭合环状DNA（cccDNA）是唯一的病毒转录模板，不受当前治疗选择的影响，构成HBV持续性的关键决定因素。需要具有针对cccDNA的显着有效性的新疗法。方法：以前，我们使用来自临床分离株（称为BPS）的复制子质粒建立HBV持久性小鼠模型，并将IL-21鉴定为有效的清除诱导剂。我们还描述了另一种基于体内产生的cccDNA模拟物的持久性小鼠模型，称为重组cccDNA（rcccDNA）。在这项工作中，使用这些模型测试了基于IL-21的基因和细胞疗法的有效性。结果：在HBV持续性的两种模型中，单次注射表达鼠IL-21的腺相关病毒（AAV）高效诱导血清中两种HBV标志物的清除，更重要的是从小鼠肝脏中清除BPS DNA和rcccDNA。机械地，IL-21诱导的清除与CD8 + T细胞的活化和肝脏浸润相关，并且CD8抗体注射对AAV-IL-21有效性产生负面影响。更值得注意的是，来自AAV-IL-21治愈小鼠的CD8 + T细胞的过继转移在受体HBV持续小鼠中产生清除。此外，通过长寿记忆保护治愈的小鼠免受再次攻击。最重要的是，从未经治疗的小鼠输注脾细胞，用IL-21蛋白离体刺激，HBV抗原也可以在未经治疗的小鼠中诱导清除。结论：这些数据证明基于IL-21的基因和细胞疗法是治疗慢性HBV感染的有效候选者，有可能通过激活的CD8 + T细胞去除携带cccDNA的肝细胞，并伴有长期保护性记忆。
关键词：

IL-21;细胞免疫;清除;乙型肝炎病毒;小鼠模型

结论：
    31281514
PMCID：
    PMC6587353
DOI：
    10.7150 / thno.35331

StephenW

http://www.thno.org/v09p3798.pdf

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