EASL2019 PS-075 AAV递送的IL-21激活CD8 + T细胞以清除HBV复制子 小鼠

StephenW

PS-075
AAV-delivered IL-21 activates CD8+ T-cells to clear HBV replicon
plasmid and cccDNA in mice
Zhongliang Shen1, Jing Liu2, Jingwen Wu1, Yuanfei Zhu2, Gaiyun Li2,
JunWang2, Mengjun Luo2, Qiang Deng2, Jiming Zhang1, Youhua Xie2.
1Huashan Hospital, Fudan University, Shanghai, China; 2School of Basic
Medical Sciences, Fudan University, Shanghai, China
Email: [email protected]
Background and aims: Chronic hepatitis B virus (HBV) infection
causes hepatitis, liver cirrhosis and hepatocellular carcinoma. HBV
covalently closed circular DNA (cccDNA) is the sole viral transcription
template in infected hepatocytes and is not cleared by current
treatment options, thus constituting a key factor underlying HBV
persistence in vivo. Previously, we established a mouse HBV
persistence model based on hydrodynamic injection of HBV replicon
plasmid and identified interleukin-21 (IL-21) as a potent regulator of
HBV clearance in mice. We also recently described another HBV
persistence mouse model based on cccDNA mimic termed recombinant
cccDNA (rcccDNA) that is produced in vivo. Novel therapeutics
with demonstrable effectiveness against cccDNA need to be
developed.
Method: Antiviral effects of IL-21 were evaluated in HBV persistence
models via adeno-associated virus (AAV)-IL-21 injection. Antibody
block and adoptive transfer of immune cells were performed to
investigate the cells involved in IL-21-mediated HBV clearance. To
determine the long-lasting memory of antiviral effects, the cured
mice were re-challenged with HBV.
Results: AAV-IL-21 treatments efficiently clears serum HBV markers
and intrahepatic HBV replicon and rcccDNA. Antibodies against CD8+
T cells delayed IL-21-mediated HBV clearance. Adoptive transfer of
splenic CD8+ T cells from the cured mice engenders clearance of HBV
persistence in acceptor mice. IL-21-induced CD8+ T cell response
harbors long-lasting memory that provides prolonged protection for
the cured mice.
Conclusion: Our results demonstrate IL-21 as a sound basis for novel
therapeutics against chronic HBV infection, with potential in
removing cccDNA-harboring hepatocytes via activated CD8+ T cell
responses and establishing subsequent long-term protection.

StephenW

PS-075
AAV递送的IL-21激活CD8 + T细胞以清除HBV复制子
小鼠中的质粒和cccDNA
沉忠良1，刘静2，吴敬文1，朱元飞2，李盖云2，
王俊2，罗孟军2，邓强2，张继明1，谢友华2
复旦大学附属华山医院，中国上海; 2基础学院
复旦大学医学院，上海，中国
电子邮件：[email protected]
背景和目的：慢性乙型肝炎病毒（HBV）感染
引起肝炎，肝硬化和肝细胞癌。 HBV
共价闭合环状DNA（cccDNA）是唯一的病毒转录
感染的肝细胞中的模板并没有被电流清除
治疗方案，因此构成了HBV的关键因素
在体内持久存在。以前，我们建立了一只小鼠HBV
基于HBV复制子水动力注射的持久性模型
质粒和鉴定的白细胞介素-21（IL-21）作为有效的调节剂
小鼠HBV清除率。我们最近也描述了另一种HBV
基于cccDNA的持久性小鼠模型称为重组体
体内产生的cccDNA（rcccDNA）。新疗法
具有明显的抗cccDNA有效性需要
发达。
方法：评估IL-21在HBV持续性中的抗病毒作用
模型通过腺相关病毒（AAV）-IL-21注射。抗体
进行免疫细胞的阻断和过继转移
研究参与IL-21介导的HBV清除的细胞。至
确定抗病毒作用的持久记忆，治愈
用HBV再次攻击小鼠。
结果：AAV-IL-21治疗有效清除血清HBV标志物
和肝内HBV复制子和rcccDNA。针对CD8 +的抗体
T细胞延迟了IL-21介导的HBV清除。收养转移
来自治愈小鼠的脾CD8 + T细胞产生HBV清除
持续受体小鼠。 IL-21诱导的CD8 + T细胞应答
拥有持久的记忆，为...提供长期保护
治好的老鼠。
结论：我们的研究结果表明IL-21是新型的良好基础
抗慢性乙型肝炎病毒感染的治疗方法
通过活化的CD8 + T细胞去除携带cccDNA的肝细胞
回应并建立后续的长期保护。

灵魂不屈

感谢分享！这个牛！