Initiation of Hepatitis B Virus Replication

乙型肝炎病毒复制的启动

• 批准号: 6771037
• 负责人: Alan McLachlan
• 金额: $ 9.39万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6771037
• 关键词: Hepadnaviridae; cancer risk; gene mutation; hepatitis B; hepatitis B virus group; liver disorder; tissue /cell culture; virus DNA; virus RNA; virus genetics; virus infection mechanism; virus replication

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) infection is a worldwide health problem. It is estimated that there are 200 to 500 million HBV chronic carriers in the world for whom, to date, there is no reliable treatment. HBV causes both acute and chronic liver disease and the estimated relative risk of primary hepatocellular carcinoma (PHC) in chronic HBV carriers is approximately 100 times greater than in uninfected individuals. Therefore, effective treatments for chronic HBV infection are required. In these studies, the mechanism(s) regulating the initial steps in the synthesis of hepatitis B virus (HBV) DNA will be investigated. HBV DNA synthesis is initiated by binding of the viral polymerase to a stem-loop structure, epsilon, located at the 5'-end of the HBV pregenomic RNA. Initially, the first three nucleotides of HBV minus-strand DNA are synthesized utilizing the amino-terminal domain of the polymerase as a primer and the bulge region of epsilon as a template. The HBV polymerase with the covalently attached trinucleotide sequence is subsequently translocated to the DR1 sequence at the 3'-end of the pregenomic RNA. HBV minus-strand DNA synthesis then proceeds by the reverse transcription of the pregenomic RNA. The mechanism(s) regulating the translocation step are unknown. Recently, a regulatory sequence element, phi, located immediately upstream of the DR1 sequence at the 3'-end of the pregnomic RNA that is important for efficient viral replication and is complementary to the 5'-half of epsilon was identified. This finding suggests that the translocation of the minus-strand primer from epsilon to DR1 might be mediated by a conformational change in the pregenomic RNA that brings the primer into proximity with the DR1 sequence at the 3'-end of the pregenomic RNA. The conservation of the complementarity between epsilon and phi in the woodchuck hepatitis virus (WHV) and the duck hepatitis B virus (DHBV) genomes also supports this contention. Therefore, the role of the complementarity between epsilon and phi in regulating HBV replication will be examined directly by mutational analysis of these sequence elements. This approach is aimed at identifying possible targets for therapeutic intervention in chronic HBV infection.

描述（由申请人提供）：乙型肝炎病毒（HBV）感染是全球健康问题。 据估计，世界上有200至5亿HBV慢性承运人，迄今为止，没有可靠的治疗方法。 HBV引起急性和慢性肝病，以及慢性HBV携带者中原发性肝细胞癌（PHC）的相对风险比未感染的个体大约100倍。 因此，需要有效治疗慢性HBV感染。 在这些研究中，将研究调节丙型肝炎病毒（HBV）DNA的初始步骤的机制。 HBV DNA合成是通过将病毒聚合酶与位于HBV前基因组RNA的5'-end的茎环结构Epsilon结合而引发的。 最初，HBV负链DNA的前三个核苷酸利用聚合酶的氨基末端结构域作为底漆，而Epsilon的凸起区域合成。 随后将其连接的三核苷酸序列的HBV聚合酶随后在前基因组RNA的3'末端转移到DR1序列。 然后，HBV减去链DNA合成通过植物前RNA的逆转录进行。 调节易位步骤的机制未知。 最近，位于妊娠RNA的3'末端上游的调节序列元素PHI对有效的病毒复制很重要，并且与Epsilon的5'半径相辅相成。 这一发现表明，减去链底漆从epsilon到DR1的易位可能是通过植物前RNA的构象变化来介导的，该植物RNA的构象变化使启动在前基因组RNA的3'末端与DR1序列接近。 在木质肝炎病毒（WHV）和鸭丙型肝炎病毒（DHBV）基因组中，epsilon和Phi之间的互补性保存也支持了这一论点。 因此，通过对这些序列元素的突变分析，将直接检查Epsilon和Phi之间互补性在调节HBV复制中的作用。 这种方法旨在确定慢性HBV感染中治疗干预的可能靶标。