Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Medical Molecular Virology, Department of Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Key Laboratory of Medical Molecular Virology, Department of Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Antiviral Res. 2021 Jun;190:105076. doi: 10.1016/j.antiviral.2021.105076. Epub 2021 Apr 15.
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.
乙型肝炎病毒（HBV）的慢性感染是肝脏疾病（如肝纤维化、肝硬化和肝细胞癌）的一个高危因素。HBV 疫苗的无应答者和低应答者不能免受 HBV 感染。实现自主或治疗诱导恢复的患者由于肝细胞中 HBV 共价闭合环状 DNA（cccDNA）的持续存在而有再激活的风险。白细胞介素 21（IL-21）是小鼠 HBV 持续感染模型中清除 HBV 的关键调节因子：基于 IL-21 的治疗方法可有效诱导 HBV 清除，并防止小鼠随后再次受到攻击。在这项研究中，我们通过使用 HBV 持续感染的小鼠模型探索了使用 IL-21 作为预防 HBV 的可能性。HBV -naive 小鼠通过注射表达小鼠 IL-21 的重组腺相关病毒（AAV-IL-21）短暂暴露于外源性 IL-21。在外源性 IL-21 蛋白和 DNA 检测不到后，通过水力注射用诱导 HBV 复制子质粒对小鼠进行挑战。通过测量血清和肝内 HBV DNA 中的病毒抗原和 DNA 标志物来分析病毒持续性。为了进行机制研究，在 HBV challenged 小鼠中通过重复腹腔内注射 CD8 单克隆抗体来阻断 CD8 T 细胞功能。在 HBV 复制子挑战后，接受 AAV-IL-21 注射的小鼠迅速清除了 HBV。相比之下，未经处理的小鼠和注射对照病毒（AAV-Ctrl）的小鼠允许 HBV 持续存在。从机制上讲，先前暴露于 IL-21 的小鼠显示出明显的肝内 CD8 T 细胞浸润，并且 CD8 阻断实验表明 CD8 T 细胞反应在功能上有助于清除。
