5’端preS1区缺失突变对乙肝病毒生物学特性和I型干扰素应答的影响及其机制研究

乙肝病毒（HBV）变异仍是阻碍乙肝治愈的一个重要因素。我们前期首次报道了一种可增强B和C基因型HBV感染性的临床突变类型：5’端preS1区缺失突变。目前尚缺乏该种突变类型对包括干扰素和核苷（酸）类似物在内的抗病毒治疗效果的影响。前期研究和既往文献提示该突变的发生与e抗原血清学转换较晚和肝硬化相关；其体外病毒转录和复制水平增高，患者血清病毒载量较高；该缺失株翻译产生类似于D基因型的、截短的preS1蛋白和聚合酶。由于聚合酶截短部分所在的末端蛋白和间隔区已被证实与抑制I型干扰素（IFN）效应相关，结合临床上IFN对D基因型HBV疗效最差，推测缺失株由于感染性和转录/复制能力更强、截短型聚合酶抑制IFN能力更强，导致其对IFN应答较差。我们拟构建高感染性HBV可调控稳转细胞系，利用HBV体外转染及感染细胞模型、模拟HBV慢性感染小鼠模型，阐明5’端preS1区缺失株的生物学特性及其对I型IFN应答效果，为存在该类突变的慢乙肝患者的治疗新策略提供理论依据。

Genetic variation of hepatitis B virus (HBV) is still a key obstacle in functional cure of chronic hepatitis B. We previously identified that 5’ preS1 deletions markedly enhance infectivity of HBV genotype B and C. However, the effects of antiviral therapy, including interferon and/or nucleoside (nucleotide) analogues remains to be explored.Based on our previous studies and published studies by others, we concluded that 5’ preS1 deletion was related to delayed HBeAg seroconversion and liver cirrhosis; the deletions would truncate preS1 protein and polymerase to become a genotype D-like form; the deletions increased HBV RNA and replicative DNA levels in vitro experiments and increased serum HBV DNA levels in patients. In addition, the terminal protein and spacer of polymerase, in which 5’ preS1 deletion is located, has been shown to inhibit host cellular response to type-I interferon (IFN). And chronic infected with genotpye D was linked with the worst response to interferon (IFN) therapy clinically. We hypothesize that the higher infectivity and transcription/replication capacity of 5’ preS1 deletion, and the higher ability of truncated polymerase to inhibit IFN system could be attributed to a poor response of 5’ preS1 deletion mutants to type-I IFNs. To verify our hypothesis, we will establish cell lines with inducible replications of high infectious HBV. We will also use HBV transfected and infected cell models, mouse model to clarify the effect of 5’ preS1 deletions on molecular biological properties and response to type-I IFNs, which may provide theoretical basis for the treatment of chronic hepatitis B patients infected with 5’ preS1 deletion mutants.