体外研究表明，序列变异有助于乙肝病毒的复制，蛋白表达

StephenW

J Virol. 2016 Aug 10. pii: JVI.01293-16. [Epub ahead of print]
In vitro studies show that sequence variability contributes to marked variation in Hepatitis B virus replication, protein expression and function observed across genotypes.Sozzi V1, Walsh R1, Littlejohn M1, Colledge D1, Jackson K1, Warner N1, Yuen L1, Locarnini SA1, Revill PA2.
Author information

• 1Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, Peter Doherty Institute of Infection and Immunity, 792 Elizabeth St, Melbourne, 3000, Victoria, Australia.
• 2Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, Peter Doherty Institute of Infection and Immunity, 792 Elizabeth St, Melbourne, 3000, Victoria, Australia. [email protected].
  

AbstractThe hepatitis B virus (HBV) exists as 9 major genotypes (A to I), one minor strain (designated J) and multiple subtypes. Marked differences in HBV natural history, disease progression and treatment response are exhibited by many of these genotypes and subtypes. For example, HBV genotype C is associated with later HBeAg seroconversion and high rates of liver cancer compared to other HBV genotypes, whereas genotype A2 is rarely associated with HBeAg negative disease or liver cancer. The reasons for these and other differences in HBV natural history are yet to be determined but could in part be due to sequence differences in the HBV genome that alter replicative capacity and / or gene expression. Direct comparative studies on HBV replication and protein expression have been limited to date, due largely to the absence of infectious HBV cDNA clones for each of the HBV genotypes present in the same genetic arrangement. We have produced replication competent infectious cDNA clones of the most common subtypes of genotypes A to D, namely A2, B2, C2, D3 and the minor strain J and compared their HBV replication phenotype using transient transfection models. We identified striking differences in HBV replicative capacity as well as hepatitis B e antigen (HBeAg) and surface (HBsAg) protein expression across genotypes, which may in part be due to sequence variability in regulatory regions of the HBV genome. Functional analysis showed that sequence differences in the major upstream regulatory region across genotypes impacted promoter activity.
IMPORTANCE: There have been very few studies directly comparing the replication phenotype of different HBV genotypes, for which there are marked differences in natural history and disease progression worldwide. We have generated replication competent 1.3 mer cDNA clones of the major genotypes A2, B2, C2, D3, as well as a recently identified strain J, and identified striking differences in replicative capacity and protein expression that may contribute to some of the observed differences in HBV natural history observed globally.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.


PMID:27512071DOI:10.1128/JVI.01293-16

StephenW

病毒学杂志。 2016年10月PII：JVI.01293-16。 [打印EPUB提前]
体外研究表明，序列变异有助于乙肝病毒的复制，蛋白表达和整个基因型观察功能存在明显的差异。
Sozzi V1，沃尔什R1，利特尔约翰M1，D1公外，杰克逊K1，华纳N1，玄L1，Locarnini SA1，Revill PA2。
作者信息

    1Victorian传染病参考实验室，皇家墨尔本医院，感染与免疫彼得·多尔蒂研究所，792伊丽莎白街，墨尔本，3000澳大利亚维多利亚州。
    2Victorian传染病参考实验室，皇家墨尔本医院，感染与免疫彼得·多尔蒂研究所，792伊丽莎白街，墨尔本，3000澳大利亚维多利亚州。 [email protected]。

抽象

乙肝病毒（HBV）的存在为9个主要的基因型（A至I），一个小的应变（指定J）和多种亚型。乙肝病毒自然史，疾病进展和治疗反应显着的差异是由许多基因型和亚型的展出。例如，HBV基因型C与后HBeAg血清转换以及相对于其他HBV基因型肝癌的高利率相关，而A2型很少HBeAg阴性疾病或肝癌有关。对于这些原因，并在HBV自然历史其它差异是尚未确定，但可以部分地是由于序列中的改变复制能力和/或基因表达的HBV基因组的差异。关于HBV复制和蛋白表达的直接比较研究已经有限迄今为止，主要是因为缺少感染HBV的cDNA克隆的每个中存在的相同的遗传结构的HBV基因型的。我们已经产生基因型A的最常见的亚型复制能力的感染性cDNA克隆至D，即A2，B2，C2，D3和次要应变J和使用瞬时转染的模型相比，它们的HBV复制表型。我们确定了乙肝病毒复制能力由于在HBV基因组的调节区序列变异性显着的差异以及乙型肝炎e抗原（HBeAg），并横跨基因型表面（HBsAg）的蛋白的表达，这可能是部分。功能分析表明，在大的上游调节区跨越基因型序列差异影响启动子活性。
重要性：

目前已经很少有研究直接比较不同HBV基因型，对此有标注全世界自然史和疾病进展的不同的复制表型。我们已经产生的主要基因型A2，B2，C2，D3，以及最近鉴定的菌株的J复制能力的1.3聚体的cDNA克隆，并确定在复制能力和蛋白表达显着的差异，可能有助于一些在观察到的差异HBV自然史全球观察。

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结论：
    27512071
DOI：
    10.1128 / JVI.01293-16