人性化鼠标
生物
乙型肝炎病毒
病毒学
病毒复制
突变体
未折叠蛋白反应
乙型肝炎表面抗原
cccDNA
肝细胞
内质网
分子生物学
免疫系统
免疫学
病毒
体外
细胞生物学
基因
生物化学
作者
Takuro Uchida,Michio Imamura,C. Nelson Hayes,Yosuke Suehiro,Yuji Teraoka,K. Ohya,Hiroshi Aikata,Hiromi Abe‐Chayama,Yuji Ishida,Chise Tateno,Yuichi Hara,Keisuke Hino,Toru Okamoto,Yoshiharu Matsuura,Hideki Aizaki,Kenjiro Wake,Michinori Kohara,T. Jake Liang,Shiro Oka,Kazuaki Chayama
出处
期刊:Hepatology
[Wiley]
日期:2023-03-10
卷期号:78 (3): 929-942
被引量:7
标识
DOI:10.1097/hep.0000000000000335
摘要
Background and Aims: Mutations within the precore (PC) and basal core promoter (BCP) regions of the HBV genome are associated with fulminant hepatitis and HBV reactivation. These mutations may enhance viral replication, but little is known about whether they directly induce damage to the liver. We investigated mechanisms of direct cytopathic effects induced by the infection with PC/BCP mutants in the absence of immune response in vitro and in vivo . Approach and Results: Mice with humanized livers and hepatocytes derived from humanized mice were infected with either wild-type or mutant-type PC/BCP HBV, and the HBV replication and human hepatocyte damage were evaluated. HBV proliferated vigorously in mice with PC/BCP-mutant infection, and the severe loss of human hepatocytes with a slight human ALT elevation subsequently occurred only in PC/BCP mutant mice. In PC/BCP mutant infection, the accumulation of HBsAg in humanized livers colocalized with the endoplasmic reticulum, leading to apoptosis through unfolded protein response in HBV-infected hepatocytes. RNA-sequencing revealed the molecular characteristics of the phenotype of PC/BCP mutant infection in a humanized mouse model. Reduced ALT elevation and higher HBV DNA levels in this model are consistent with characteristics of HBV reactivation, indicating that the hepatocyte damage in this model might mimic HBV reactivation followed by hepatocyte damage under immunosuppressive conditions. Conclusion: PC and BCP mutations were associated with enhanced viral replication and cell death induced by ER stress using HBV infection models. These mutations might be associated with liver damage in patients with fulminant hepatitis or HBV reactivation.
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