乙肝病毒基因组编码4种不同长度(3.5-kb、2.4-kb、2.1-kb和0.7-kb)的mRNA,这些RNA具有共同的3'末端和不同的5'末端。我们发现某些核心启动子突变引起3.5-kb RNA（编码核心抗原）转录增强并促进基因组复制，但却减弱由2.1-kb RNA编码的S蛋白表达。此外，D基因型比A基因型毒株也高表达核心抗原而低表达S蛋白。因此推测3.5-kb RNA有可能干扰下游的启动子活性，从而抑制2.1-kb RNA转录。本项目将以核心启动子变异和A/D基因型为切入点验证转录干扰假说。鉴于核心启动子突变株与D基因型毒株都是临床免疫清除期的优选株，阐明乙肝病毒的转录调控新机制将为干预持续感染，优化临床治疗措施提供理论基础。

The hepatitis B virus (HBV) genome produces four classes of mRNA (3.5-kb, 2.4-kb, 2.1-kb, 0.7-kb) with different 5' ends but identical 3' end. We found some core promoter mutations not only increased transcription of the 3.5-kb RNA (the mRNA for core protein) and consequently genome replication, but also diminished expression of the small envelope protein derived from the 2.1-kb RNA. Similarly, genotype D isolates displayed more efficient core protein expression and genome replication than genotype A isolates but lower level of small envelope protein expression. These findings led us to propose that that the 3.5-kb RNA interferes with transcription of the downstream 2.1-kb RNA transcription unit through promoter occlusion. In this application we will use core promoter mutations and genotypes A and D to formally test the transcriptional interference hypothesis. Considering that both core promoter mutations and genotype D are selected during the immune clearance phase, elucidating a novel mechanism in HBV RNA transcription will provide theoretical foundations for interruption of persistent infection and optimization of therapeutic approaches.

乙肝病毒基因组编码4种不同长度(3.5-kb、2.4-kb、2.1-kb和0.7-kb)的mRNA,这些RNA具有共同的3’末端和不同的5’末端。我们发现某些核心启动子突变引起3.5-kb RNA（编码核心抗原）转录增强并促进基因组复制，但却减弱由2.1-kb RNA编码的S蛋白表达。此外，D基因型比A基因型毒株也高表达核心抗原而低表达S蛋白。因此推测3.5-kb RNA有可能干扰下游的启动子活性，从而抑制2.1-kb RNA转录。本项目将以核心启动子变异和A/D基因型为切入点验证转录干扰假说。鉴于核心启动子突变株与D基因型毒株都是临床免疫清除期的优选株，阐明乙肝病毒的转录调控新机制将为干预持续感染，优化临床治疗措施提供理论基础。