乙型肝炎病毒的信封基因对基因型B和基因型C分离株之间的差

StephenW

Viruses. 2017 Mar 28;9(4). pii: E62. doi: 10.3390/v9040062.
The Envelope Gene of Hepatitis B Virus Is Implicated in Both Differential Virion Secretion and Genome Replication Capacities between Genotype B and Genotype C Isolates.
Jia H1, Qin Y2, Chen C3, Zhang F4, Li C5, Zong L6, Wang Y7, Zhang J8, Li J9, Wen Y10, Tong S11,12.
Author information

1    Key Lab of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. [email protected].
2    Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200032, China. [email protected].
3    Key Lab of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. [email protected].
4    Key Lab of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. [email protected].
5    Key Lab of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. [email protected].
6    Key Lab of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. [email protected].
7    Key Lab of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. [email protected].
8    Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200032, China. [email protected].
9    Liver Research Center, Rhode Island Hospital, Warren Alpert School of Medicine, Brown University, Providence, RI 02903, USA. [email protected].
10    Key Lab of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. [email protected].
11    Key Lab of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. [email protected].
12    Liver Research Center, Rhode Island Hospital, Warren Alpert School of Medicine, Brown University, Providence, RI 02903, USA. [email protected].

Abstract

Chronic infection by hepatitis B virus (HBV) genotype C is associated with a prolonged replicative phase and an increased risk of liver cancer, compared with genotype B infection. We previously found lower replication capacity but more efficient virion secretion by genotype C than genotype B isolates. Virion secretion requires interaction between core particles and ENVELOPE proteins. In the present study, chimeric constructs between genotype B and genotype C clones were generated to identify the structural basis for differential virion secretion. In addition to dimeric constructs, we also employed 1.1mer constructs, where the cytomegalovirus (CMV) promoter drove pregenomic RNA transcription. Through transient transfection experiments in Huh7 cells, we found that exchanging the entire envelope gene or just its S region could enhance virion secretion by genotype B clones while diminishing virion secretion by genotype C. Site-directed mutagenesis established the contribution of genotype-specific divergence at codons 108 and 115 in the preS1 region, as well as codon 126 in the S region, to differential virion secretion. Surprisingly, exchanging the envelope gene or just its S region, but not the core gene or 3' S region, could markedly increase intracellular replicative DNA for genotype C clones but diminish that for genotype B, although the underlying mechanism remains to be clarified.
KEYWORDS:

core gene; envelope gene; genome replication; genotype; hepatitis B virus; virion secretion

PMID:
    28350327
DOI:
    10.3390/v9040062

StephenW

病毒2017年3月28日; 9（4）。皮埃埃：E62。 doi：10.3390 / v9040062。
乙型肝炎病毒的信封基因对基因型B和基因型C分离株之间的差异病毒分泌和基因组复制能力都有影响。
贾，秦，Y2，陈C3，张F4，李C5，宗L6，王毅7，张杰8，李杰9，文Y 10，唐S11,12。
作者信息

复旦大学基础医学院医学分子病毒学重点实验室，上海200032。 [email protected]。
2复旦大学华山医院感染科，上海200032。 [email protected]。
3复旦大学基础医学院医学分子病毒学重点实验室，上海200032。 [email protected]。
复旦大学基础医学院医学分子病毒学重点实验室，上海200032。 [email protected]。
复旦大学基础医学院医学分子病毒学重点实验室，上海200032。 [email protected]。
6复旦大学基础医学院医学分子病毒学重点实验室，上海200032。 [email protected]。
复旦大学基础医学院医学分子病毒学重点实验室，上海200032。 [email protected]。
8复旦大学华山医院感染科，上海200032。 [email protected]。
9肝脏研究中心，罗德岛医院，沃伦阿尔珀蒂医学院，布朗大学，普罗维登斯，RI 02903，美国。 [email protected]
复旦大学基础医学院医学分子病毒学重点实验室，上海200032。 [email protected]。
11复旦大学基础医学院医学分子病毒学重点实验室，上海200032。 [email protected]
12肝脏研究中心，罗德岛医院，沃伦阿尔珀蒂医学院，布朗大学，普罗维登斯，RI 02903，美国。 [email protected]

抽象

与B型感染相比，乙型肝炎病毒（HBV）基因型C的慢性感染与延长的复制期和肝癌风险增加相关。我们以前发现基因型C比基因型B分离株更低的复制能力，但效率更高的病毒粒子分泌。病毒分泌需要核心颗粒和ENVELOPE蛋白质之间的相互作用。在本研究中，产生基因型B和基因型C克隆之间的嵌合构建体，以鉴定差异病毒粒子分泌的结构基础。除二聚体构建体外，我们还使用1.1mer构建体，其中巨细胞病毒（CMV）启动子驱动前基因组RNA转录。通过Huh7细胞的瞬时转染实验，我们发现交换整个包膜基因或其S区域可以增强基因型B克隆的病毒体分泌，同时通过基因型C降低病毒粒子分泌。定点突变确定了基因型特异性分歧在preS1区域中的密码子108和115以及S区中的密码子126到差异的病毒粒子分泌。令人惊讶的是，交换包膜基因或仅仅是其S区，而不是核心基因或3'S区域，可以显着增加基因型C克隆的细胞内复制DNA，但是减少基因型B，尽管底层机制仍有待澄清。
关键词：

核心基因;包膜基因;基因组复制;基因型;乙型肝炎病毒;病毒体分泌

PMID：
    28350327
DOI：
    10.3390 / v9040062

MP4

闻玉梅院士