乙型肝炎前核/核心相关抗原的表征

StephenW

Characterization of Hepatitis B Precore/Core-Related Antigens
Xupeng Hong, Laurie Luckenbaugh, Megan Mendenhall, Renae Walsh, Liza Cabuang, Sally Soppe, Peter A. Revill, Dara Burdette, Becket Feierbach, William Delaney, Jianming Hu
J.-H. James Ou, Editor
DOI: 10.1128/JVI.01695-20

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ABSTRACT

Current therapies rarely cure chronic hepatitis B virus (HBV) infection due to the persistence of the viral episome, the covalently closed circular DNA (cccDNA), in hepatocytes. The hepatitis B virus core-related antigen (HBcrAg), a mixture of the viral precore/core gene products, has emerged as one potential marker to monitor the levels and activities of intrahepatic cccDNA. In this study, a comprehensive characterization of precore/core gene products revealed that HBcrAg components included the classical hepatitis B virus core antigen (HBc) and e antigen (HBeAg) and, additionally, the precore-related antigen, PreC, retaining the N-terminal signal peptide. Both HBeAg and PreC antigens displayed heterogeneous proteolytic processing at their C termini resulting in multiple species, which varied with viral genotypes. HBeAg was the predominant form of HBcrAg in HBeAg-positive patients. Positive correlations were found between HBcrAg and PreC, between HBcrAg and HBeAg, and between PreC and HBeAg but not between HBcrAg and HBc. Serum HBeAg and PreC shared similar buoyant density and size distributions, and both displayed density and size heterogeneity. HBc, but not HBeAg or PreC antigen, was found as the main component of capsids in DNA-containing or empty virions. Neither HBeAg nor PreC protein was able to form capsids in cells or in vitro under physiological conditions. In conclusion, our study provides important new quantitative information on levels of each component of precore/core gene products as well as their biochemical and biophysical characteristics, implying that each component may have distinct functions and applications in reflecting intrahepatic viral activities.

IMPORTANCE Chronic hepatitis B virus (HBV) infection afflicts approximately 257 million people, who are at high risk of progressing to chronic liver diseases, including fibrosis, cirrhosis, and hepatocellular carcinoma. Current therapies rarely achieve cure of HBV infection due to the persistence of the HBV episome, the covalently closed circular DNA (cccDNA), in the nuclei of infected hepatocytes. Peripheral markers of cccDNA levels and transcriptional activities are urgently required to guide antiviral therapy and drug development. Serum hepatitis B core-related antigen (HBcrAg) is one such emerging peripheral marker. We have characterized the components of HBcrAg in HBV-infected patients as well as in cell cultures. Our results provide important new quantitative information on levels of each HBcrAg component, as well as their biochemical and biophysical characteristics. Our findings suggest that each HBcrAg component may have distinct functions and applications in reflecting intrahepatic viral activities.

    Copyright © 2021 American Society for Microbiology.

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StephenW

乙型肝炎前核/核心相关抗原的表征
Xupeng Hong，Laurie Luckenbaugh，Megan Mendenhall，Renae Walsh，Liza Cabuang，Sally Soppe，Peter A.Revill，Dara Burdette，Becket Feierbach，William Delaney，胡建明
J.-H.詹姆斯·欧（James Ou），编辑
DOI：10.1128 / JVI.01695-20

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抽象

由于肝细胞中病毒附加体（共价闭合环状DNA（cccDNA））的持续存在，当前的疗法很少能治愈慢性乙型肝炎病毒（HBV）感染。乙型肝炎病毒核心相关抗原（HBcrAg）是病毒前核心/核心基因产物的混合物，已成为监测肝内cccDNA水平和活性的一种潜在标记。在这项研究中，对前核心/核心基因产物的全面表征表明，HBcrAg成分包括经典的乙型肝炎病毒核心抗原（HBc）和e抗原（HBeAg），此外，前核心相关抗原PreC保留了N-末端信号肽。 HBeAg和PreC抗原在其C末端均显示出异质蛋白水解过程，从而导致多种物种，这些物种随病毒基因型而变化。 HBeAg是HBeAg阳性患者中HBcrAg的主要形式。 HBcrAg与PreC之间，HBcrAg与HBeAg之间，PreC与HBeAg之间呈正相关，而HBcrAg与HBc之间无正相关。血清HBeAg和PreC具有相似的浮力密度和大小分布，并且显示出密度和大小异质性。发现HBc，而不是HBeAg或PreC抗原，是含有DNA或空的病毒体中衣壳的主要成分。在生理条件下，HBeAg和PreC蛋白均无法在细胞中或体外形成衣壳。总之，我们的研究提供了有关前核心/核心基因产物各成分的水平及其生化和生物物理特性的重要的新定量信息，这意味着各成分在反映肝内病毒活性方面可能具有不同的功能和应用。

重要信息慢性乙型肝炎病毒（HBV）感染折磨着大约2.57亿人，他们有发展为慢性肝病（包括纤维化，肝硬化和肝细胞癌）的高风险。由于被感染的肝细胞核中存在HBV附加体，共价闭合的环状DNA（cccDNA），因此目前的疗法很少能治愈HBV感染。迫切需要cccDNA水平和转录活性的周围标志物来指导抗病毒治疗和药物开发。血清乙肝核心相关抗原（HBcrAg）就是一种新兴的外周标志物。我们已经在HBV感染患者以及细胞培养物中表征了HBcrAg的成分。我们的结果提供了有关每种HBcrAg成分水平及其生化和生物物理特性的重要新定量信息。我们的发现表明，每种HBcrAg成分在反映肝内病毒活性方面可能具有不同的功能和应用。

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