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Hepatitis B virus e antigen expression

乙型肝炎病毒e抗原表达

基本信息

批准号：
6722792
负责人：
SHUPING TONG
金额：
$ 7.7万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2006-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6722792
关键词：
gene expression gene mutation genetic promoter element genetic strain hepatitis B antigens hepatitis B virus group host organism interaction tissue /cell culture virus genetics virus replication

项目摘要

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) infects nearly 1/10th of the world population and causes severe liver diseases including cancer. The e antigen (HBeAg) is a secreted soluble protein that promotes immune tolerance during perinatal infection and buffers immunity against HBcAg. The corresponding anti-HBe immune response plays a critical role in the clearance of HBV infection. Therefore, following seroconversion from HBeAg antigenemia to anti-HBe, HBV escape mutants with reduced or no HBeAg production often replace wild-type HBV genomes. The core promoter mutants have various nucleotide changes around positions 1750 -1770 of the HBV genome, and the most common mutations at 1762 and 1764 are known to reduce HBeAg expression at the transcriptional level. The precore mutants have nonsense or frameshift mutations in the HBeAg coding sequence and terminate HBeAg expression at the translational level. Considering the critical importance of HBeAg and anti-HBe in shaping the outcome of HBV infection, we wish to uncover novel regulatory mechanisms for HBeAg expression. In this regard, perinatally infected South African patients seroconvert from HBeAg to anti-HBe at a much accelerated pace than similarly infected Asian patients. Interestingly, the South African HBV variants often harbor two or three point mutations near the precore initiation codon. We plan to verify whether the mutations cause leaky scanning to reduce HbeAg translation. Second, HBeAg maturation requires double proteolytic cleavage events in the secretory pathway. The first cleavage occurs in endoplasmic reticulum to remove the N-terminal signal peptide of 19 residues. A Val to Phe missense mutation at residue 17 is frequently detected in HBV genomes isolated from seroconverted patients. Since an aromatic residue at the -3 position of cleavage site is forbidden, we will test whether this mutation impairs HBeAg cleavage and secretion. Third, we recently identified several naturally occurring core promoter mutants with wild-type level of HBeAg production. Based on the results of preliminary mapping experiments, we will determine whether the number and position of core promoter mutations influence the level of HBeAg expression, and whether missense mutations in the HBeAg coding sequence also regulate HBeAg level. This study promises to verify and identify novel mechanisms regulating HBeAg expression, which has a major impact on the outcome of HBV infection.

描述（由申请人提供）：B型肝炎病毒（HBV）感染了近1/10的世界人口，并导致严重的肝脏疾病，包括癌症。 e抗原（HBeAg）是一种分泌的可溶性蛋白，在围产期感染期间促进免疫耐受并缓冲针对HBcAg的免疫。相应的抗HBe免疫应答在HBV感染的清除中起着关键作用。因此，在从HBeAg抗原血症血清转化为抗-HBe后，HBeAg产生减少或不产生的HBV逃逸突变体通常取代野生型HBV基因组。核心启动子突变体在HBV基因组的1750 - 1770位置附近具有各种核苷酸变化，并且已知在1762和1764处的最常见突变在转录水平上降低HBeAg表达。前C突变体在HBeAg编码序列中具有无义或移码突变，并在翻译水平上终止HBeAg表达。考虑到HBeAg和抗-HBe在形成HBV感染结果中的关键重要性，我们希望揭示HBeAg表达的新调控机制。在这方面，围产期感染的南非患者从HBeAg血清转化为抗-HBe的速度比类似感染的亚洲患者快得多。有趣的是，南非的HBV变异体通常在前C起始密码子附近具有两个或三个点突变。我们计划验证这些突变是否会导致漏扫描以减少HBeAg翻译。其次，HBeAg成熟需要分泌途径中的双重蛋白水解裂解事件。第一次切割发生在内质网中，以去除N端19个残基的信号肽。在从血清转换患者分离的HBV基因组中经常检测到残基17处的瓦尔至Phe错义突变。由于切割位点-3位的芳香残基是禁止的，我们将测试该突变是否会损害HBeAg的切割和分泌。第三，我们最近发现了几个天然存在的核心启动子突变体与野生型水平的HBeAg生产。基于初步定位实验的结果，我们将确定核心启动子突变的数量和位置是否影响HBeAg表达水平，以及HBeAg编码序列中的错义突变是否也调节HBeAg水平。这项研究有望验证和确定新的机制调节HBeAg的表达，这对HBV感染的结果有重大影响。