Key Laboratory of Medical Molecular Virology (MOE/MOH) and Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 131 Dong'An Road, 200032, Shanghai, People's Republic of China.
Department of Infectious Diseases, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, 200040, Shanghai, People's Republic of China.
Nat Commun. 2017 Dec 14;8(1):2119. doi: 10.1038/s41467-017-02304-7.
Hepatitis B virus (HBV) generally causes self-limiting infection in immunocompetent adults, but establishes chronic infection in some adults and in most maternally infected infants. Factors determining clearance versus persistence are not fully understood. Hydrodynamic injection (HDI) of HBV replicon plasmid via tail vein generally results in quick clearance in immunocompetent adult mice. Here, we report the identification of strain-specific persistence of HBV in mice: one genotype B strain, designated BPS, persisted up to 33 weeks in ~50% of HDI mice. BPS persistence requires viral replication and multiple viral features. Compared to quickly cleared strains, BPS fails to induce robust post-exposure serum IL-21/IL-33 responses. Injection of IL-21-expressing or IL-33-expressing plasmids facilitates clearance of pre-established BPS persistence and protects cured mice from BPS re-challenge. IL-21 and IL-33 also induce clearance of pre-established HBV persistence in another mouse model. These data reveal IL-21 and IL-33 as potent regulators of HBV clearance and valid drug candidates.
乙型肝炎病毒 (HBV) 通常在免疫功能正常的成年人中引起自限性感染，但在一些成年人和大多数母婴感染的婴儿中会导致慢性感染。决定清除与持续存在的因素尚未完全阐明。通过尾静脉进行 HBV 复制子质粒的水力动力学注射（HDI）通常会导致免疫功能正常的成年小鼠迅速清除。在这里，我们报告了在小鼠中鉴定出 HBV 的株特异性持续存在：一种基因型 B 株，命名为 BPS，在约 50%的 HDI 小鼠中持续存在长达 33 周。BPS 的持续存在需要病毒复制和多种病毒特征。与快速清除的菌株相比，BPS 无法诱导强烈的暴露后血清 IL-21/IL-33 反应。注射表达 IL-21 或 IL-33 的质粒可促进预先建立的 BPS 持续存在的清除，并保护治愈的小鼠免受 BPS 的再次攻击。IL-21 和 IL-33 还可诱导另一种小鼠模型中预先建立的 HBV 持续存在的清除。这些数据揭示了 IL-21 和 IL-33 作为 HBV 清除的有效调节剂和有效的候选药物。
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