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乙型肝炎病毒复制性增强的机理研究
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乙型肝炎病毒（Hepatitis B Virus, HBV）的感染可表现为无症状携带、急性肝炎、慢性肝炎，并可发展为肝硬化与肝癌。近年来发现，除机体免疫应答外，HBV毒株的生物学特性与致病性相关。研究表明HBV复制增强常导致毒力增强。本研究从我国天然存在的HBV株入手，研究HBV复制性增强的机理。这一研究不仅有助于阐明HBV的致病机制，还可为研制新的抗HBV药物奠定基础。 在本研究的第一部分，在从两例慢性乙肝患者血清中分离得到两株复制能力差异显著的全基因组HBV DNA基础上，采用构建高低复制株聚合酶功能区嵌合体及PCR定位点突变的研究策略，分析聚合酶的基因结构与复制性增强的机制。结果表明，位于逆转录酶功能区（RT区）的HBV DNA聚合酶第652位氨基酸Ser?Pro突变是导致HBV复制增强的决定性因素。蛋白三维结构模拟分析证实652位氨基酸Pro?Ser突变可使聚合酶的活性受损。HBV DNA聚合酶652位氨基酸是本研究发现的新的复制性功能位点，为研制针对该位点的抗HBV治疗药物奠定了基础。 本研究的第二部分从全基因组角度研究我国HBV相关性肝癌患中HBV复制的特性。通过对一例在四年间由HBsAg阳性无症状携带者发展至肝癌的患者的11株HBV全基因组分析，发现肝癌患者肝内全基因组HBV DNA复制能力高。此外还发现肝组织内的2.2Kb HBV剪接变异体具有促进全基因组HBV复制的作用。肝内HBV全基因组及2.2Kb剪接变异体这种复制性增强特性可能是HBV持续性复制并导致我国HBV相关肝癌患者多见的重要原因之一。 关键词：乙型肝炎病毒 复制 RNA剪接 基因变异 肝癌 中图分类号：R373.2＋1 Studies on The Mechanisms of Enhanced Replicative Efficiency of Hepatitis B Virus ABSTRACT Hepatitis B virus (HBV) infection has a broad clinical manifestations including asymptomatic carrier, acute hepatitis, chronic hepatitis, which may lead to cirrhosis and hepatocellular carcinoma. In the past decade , studies showed that aside from host immue responses, the biological characteristics of HBV strains also contributed to the pathogenesis of HBV infection. Enhanced replication could display enhanced virulence of HBV strains. In this study, naturally occurring HBV strains were used to study the mechanisms of enhanced replicative efficiency. This study not only would help for deep understanding the pathogenesis of HBV, but also could be informative for development of new anti-HBV therapeutic drugs. II-1 The first part of this study was based on two HBV strains with different replicative efficiency, which were isolated separately from the sera of two patients with chronic hepatitis. Strategies to generate chimeric genome by polymerase chain reaction and site-directed mutagenesis were employed for characterization of the functional domain responsible for different replication competence between these two HBV strains. Results showed that a single amino acid substitution from serine to proline in position 652 within the RT region of polymerase gene was responsible for such striking difference between these two HBV strains. Moreover, three dimensional analysis of RT region of HBV polymerase showed that amino acid substitution from proline to serine in position 652 could impair the polymerase activity. Therefore, the 652 amino acid in the polymerase protein is a newly identified functional site associated with enhanced replication. This finding can be used to develop new anti-HBV therapeutics drugs. In the second part of this study, full-length HBV genomes were collected from hepatocellular carcinoma (HCC) tissues to study their replicative efficiency. When isolates were collected from a patient who was an HBsAg positive asymptomatic carrier who developed HCC in four years, it was showed that full-length HBV isolated from the liver tissues of HCC patients exhibited higher replicative competence than those from the sera samples. In addition, it was also showed that 2.2Kb splicing variants of HBV in liver tissues could enhance the repliation of its full-length counterpart. Both enhanced replication of full-length HBV and the 2.2Kb splicing variants might contribute to the persistence of HBV infection which could be one of the factors involved in the high incidence of hepatocellular carcinoma in China. |
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