北京大学李彤/向宽辉课题组建立乙型肝炎病毒和丙型肝炎病毒共感染的细胞模型

HBV和HCV感染一直是我国乃至世界的严重公共卫生问题。HBV/HCV共感染情况很常见，我国慢性HCV感染合并HBV感染的流行率约为8%-13%。HBV/HCV共感染要比单感染更容易导致肝脏损害，更容易发生肝纤维化、肝硬化及肝细胞癌。2021年3月14日，北京大学基础医学院病原生物学系及感染病中心李彤/向宽辉团队在Antiviral Research发表乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）共感染最新研究成果，该研究成功建立了乙肝病毒和丙肝病毒共感染细胞模型。 这为两种肝炎病毒共感染机制的深入研究奠定基础。

一般而言，HBV/HCV共感染下，HCV复制占主导地位，HBV的复制受到抑制。对于HCV和HBV在细胞内到底是如何相互作用的，到目前还未知，其中一个重要原因是没有一个好的细胞感染模型用于HBV/HCV共感染研究。

该团队基于HepG2细胞，通过过表达HBV受体NTCP及HCV感染相关分子，筛选出一株可以支持HBV/HCV共感染的细胞株（HepG2-NTCP/CD81/Mir122）。此细胞不仅支持HBV/HCV单感染，而且还支持HBV/HCV在同一细胞内同时感染。两种病毒相互不影响感染效率，但是共感染后HBV的复制能力明显下降，与临床报道一致。此外，该细胞模型还可以模拟临床用药后HBV复制反弹的机制研究，为解释其机制及优化临床用药等提供理论基础。

该团队的硕士研究生张凯和博士研究生赖鑫源为论文的共同第一作者，向宽辉副研究员、李彤副教授和庄辉教授为论文共同通讯作者。该研究工作同时得到了北京大学第三医院张佳佳医生及北京佑安医院的李传云医生的支持和帮助。

附文献信息：

  • 题目：A novel cell culture model reveals the viral interference during hepatitis B and C virus coinfection.

  • DOI：10.1016/j.antiviral.2021.105061

  • Highlights：（1）This novel cell model fully supports HBV and HCV coinfection.（2）HBV replication was suppressed by HCV and rebounded during the interferon α and direct-acting antiviral drugs treatment.（3）HBV core promoter and S promoter II activities were inhibited when coinfected with HCV.（4）This cell model provides opportunity to study molecular details of the interaction of HBV and HCV in coinfected cells.

  • Abstract: Coinfection of hepatitis B virus (HBV) and hepatitis C virus (HCV) may result in severe liver disease and frequent progression to cirrhosis and hepatocellular carcinoma. Clinical evidence suggests that HBV replication is suppressed by replicating HCV and often rebounds after treatment with drugs against HCV. Thus, a highly efficient cell culture system permissive for HBV/HCV would facilitate investigation on the interaction and pathogenesis after coinfection. Here we reported a robust HBV/HCV coinfection cell culture model by overexpressing human sodium-taurocholate cotransporting polypeptide (NTCP), CD81 and Mir122 into HepG2 cells and investigated interactions between HBV and HCV. In this system, HepG2-NTCP/CD81/Mir122 cells not only supported robust infection and replication of HBV and HCV, but also allowed HBV/HCV coinfection in the single cell level. Our result showed cells with replicating HBV still supported HCV infection. However, HBV replication was suppressed by HCV through the inhibition of HBV core promoter and S promoter II activity, and this inhibition was attenuated by the interferon alpha (IFNα) treatment, suggesting HCV influence on HBV at transcriptional level. Coinfection of HBV/HCV in this system did not block IFN stimulated genes expression. Inhibition of HCV by direct-acting antiviral drugs restored HBV replication and expression of viral genes. Conclusions: HepG2-NTCP/CD81/Mir122 fully supports HBV/HCV coinfection, replication and interaction. This novel cell model offers a platform to advance our understanding of the molecular details of the interaction, pathogenesis and outcomes of HBV/HCV coinfection.

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