Prior transient exposure to interleukin-21 delivered by recombinant adeno-associated virus vector protects mice from hepatitis B virus persistence.
Prior transient exposure to interleukin-21 delivered by recombinant adeno-associated virus vector protects mice from hepatitis B virus persistence.
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DOI：
10.1016/j.antiviral.2021.105076
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发表时间：
2021-04
影响因子：
7.6
通讯作者：
Zhongliang Shen;Zixiang Gao;Chenjian Gu;Jingwen Wu;Jinyu Wang;Jiming Zhang;Youhua Xie;Jing Liu
中科院分区：
文献类型：
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作者：
Zhongliang Shen;Zixiang Gao;Chenjian Gu;Jingwen Wu;Jinyu Wang;Jiming Zhang;Youhua Xie;Jing Liu
B型肝炎病毒（HBV）慢性感染是导致肝纤维化、肝硬化、肝细胞癌等肝脏疾病的高危因素。对HBV疫苗无应答者和低应答者不能免受HBV感染。由于肝细胞中HBV共价闭合环状DNA（cccDNA）的持续存在，实现自主或治疗诱导恢复的患者存在再激活的风险。白细胞介素21（IL-21）是HBV持续性小鼠模型中HBV清除的关键调节因子：基于IL-21的治疗有效诱导HBV清除并保护小鼠免受随后的再攻击。在这项研究中，我们探讨了使用IL-21作为预防HBV的可能性，通过使用小鼠模型的HBV持续存在。通过注射表达小鼠IL-21的重组腺相关病毒（AAV-IL-21）使HBV未感染小鼠瞬时暴露于外源性IL-21。在外源性IL-21蛋白和DNA变得不可检测后，通过流体动力学注射用持续诱导HBV复制子质粒攻击小鼠。通过测定血清和肝内HBV DNA中的病毒抗原和DNA标志物来分析病毒持续性。对于机制研究，通过在HBV攻击的小鼠中重复腹膜内注射CD 8单克隆抗体来阻断CD 8 +T细胞功能。注射AAV-IL-21的小鼠在HBV复制子攻击后快速清除HBV。相比之下，未处理的小鼠和注射对照病毒（AAV-Ctrl）的小鼠允许建立HBV持久性。从机制上讲，先前暴露于IL-21的小鼠显示出显著的肝内CD 8 +T细胞浸润，并且CD 8阻断实验证明CD 8 +T细胞应答在功能上有助于清除。
Chronic infection of hepatitis B virus (HBV) is a high risk factor for hepatic diseases, such as liver fibrosis, cirrhosis and hepatocellular carcinoma. Non-responders and hyporesponders to HBV vaccine are not protected from HBV infection. Patients that achieve autonomous or treatment-induced recovery are at risk of reactivation due to persistence of HBV covalently closed circular DNA (cccDNA) in hepatocytes. Interleukin 21 (IL-21) is a key regulator of HBV clearance in mouse models of HBV persistence: IL-21-based therapies effectively induces HBV clearance and protects mice from subsequent re-challenge. In this study, we explore the possibility of using IL-21 as prophylaxis against HBV by using mouse models of HBV persistence. HBV-naïve mice were transiently exposed to exogenous IL-21 through injection with recombinant adeno-associated virus expressing mouse IL-21 (AAV-IL-21). After extraneous IL-21 protein and DNA had become undetectable, mice were challenged with persistence-inducing HBV replicon plasmid through hydrodynamic injection. Viral persistence was analyzed by measuring viral antigens and DNA markers in serum and intrahepatic HBV DNA. For mechanistic studies, CD8+T cell functions were blocked by repeated intraperitoneal injections of CD8 monoclonal antibodies in HBV-challenged mice. AAV-IL-21-injected mice quickly cleared HBV after HBV replicon challenge. In contrast, untreated mice and mice injected with control virus (AAV-Ctrl) allowed establishment of HBV persistence. Mechanistically, mice with prior IL-21 exposure displayed marked intrahepatic CD8+T cell infiltrations, and CD8 blocking experiments demonstrated that CD8+T cell responses functionally contributed toward clearance.