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）：丙型肝炎病毒（HBV）感染了近1/10的世界人口，并引起包括癌症在内的严重肝病。 E抗原（HBEAG）是一种分泌的可溶性蛋白，可在围产期感染期间促进免疫耐受性，并缓冲抗HBCAG的免疫力。相应的抗HBE免疫反应在清除HBV感染中起着至关重要的作用。因此，在从HBEAG抗原血症到抗HBE的血清转化后，HBV逃脱了降低或没有HBEAG产生的突变体经常取代野生型HBV基因组。核心启动子突变体在位置1750 -1770的HBV基因组周围具有各种核苷酸变化，而已知1762和1764年最常见的突变可在转录水平上降低HBEAG表达。前孔突变体在HBEAG编码序列中具有废话或移码突变，并在翻译水平上终止HBEAG表达。考虑到HBEAG和Anti-HBE在塑造HBV感染结果中的重要性，我们希望发现新颖的调节机制以表达HBEAG的表达。在这方面，与类似地感染的亚洲患者相比，围产期感染的南非患者从HBEAG从HBEAG到抗HBE。有趣的是，南非的HBV变体通常在预处理启动密码子附近携带两个或三个突变。我们计划验证突变是否引起漏扫描以减少HBEAG翻译。其次，HBEAG成熟需要分泌途径中的双蛋白水解裂解事件。第一个切割发生在内质网中，以去除19个残基的N末端信号肽。从血清转化患者分离出的HBV基因组中经常检测到残基17处的PHE错义突变。由于禁止在裂解位点的-3位置的芳族残留物，我们将测试该突变是否会损害HBEAG的裂解和分泌。第三，我们最近确定了几个天然存在的核心启动子突变体，其HBEAG产生水平。根据初步映射实验的结果，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调节HBEAG表达的新型机制，这对HBV感染的结果产生了重大影响。