HBV replication and persistence in mouse models

描述(由申请人提供)： 乙肝病毒是一种嗜肝病毒，可引起包括急、慢性肝炎和肝细胞癌在内的严重肝病。世界上约有3.5亿人长期感染这种病毒，每年导致50万至100万人死亡。乙肝病毒的宿主范围非常窄，这极大地阻碍了它的研究。然而，近年来几种小鼠模型的发展已经部分克服了这一问题，并为理解乙肝病毒的复制和发病机制产生了许多重要的发现。通过将雌性半合子转基因小鼠与雄性自然小鼠杂交，我们获得了非转基因小鼠。当这些非转基因小鼠通过流体动力注射的方式注射乙肝病毒基因组DNA时，乙肝病毒在小鼠肝脏中的复制持续了长达7个月，类似于乙肝病毒在患者体内的垂直传播。临床上，超过90%的乙肝病毒携带者所生的婴儿将成为乙肝病毒携带者。这种“垂直传播”是乙肝病毒最常见的传播方式，尤其是在乙肝流行区，也是慢性乙肝病毒感染的最重要原因。因此，我们的小鼠模型为我们提供了一个独特的机会来研究垂直传播后乙肝病毒持续存在的机制。我们将利用这个小鼠模型来研究HBVe抗原(HBeAg)和一类在基本核心启动子(BCP)中携带双核苷酸突变、HBeAg表达水平降低的HBVe抗原突变株在乙肝病毒持续感染和致病中的作用。此外，我们最近的研究表明，病毒接种量和干扰素的大小也会影响乙肝病毒的持久性。因此，我们还将研究这些因素在乙肝病毒持续存在中的作用。我们提出的研究将为我们了解乙肝病毒的复制和持久性提供重要的信息，并促进对乙肝患者治疗的发展。

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) is a hepatotropic virus that can cause severe liver diseases including acute and chronic hepatitis and hepatocellular carcinoma (HCC). There are ~350 million people in the world that are chronically infected by this virus, resulting in 0.5-1 million deaths every year. HBV has a very narrow host range, which has greatly hampered its research. The development of several mouse models in recent years, however, has partially overcome this problem and generated many important findings for understanding HBV replication and pathogenesis. By crossing female hemizygous HBV transgenic mice to male na¿ve mice, we were able to obtain non-transgenic mouse pups. When these non-transgenic mouse pups were injected with the HBV genomic DNA by hydrodynamic injection, the HBV replication persisted in the mouse liver for up to seven months, resembling the vertical transmission of HBV in patients. Clinically, over 90% of babies born to women who are HBV carriers will become HBV carriers. This "vertical transmission" is the most common way of HBV transmission, particularly in HBV endemic areas, and the most important reason for chronic HBV infection. Our mouse model thus provides us with a unique opportunity to study the mechanism of HBV persistence after vertical transmission. We will use this mouse model to investigate the role of the HBV e antigen (HBeAg), which is thought to play a very important role in establishing persistent infection after the vertical transmission, and a class of HBV mutants, which carry a double-nucleotide mutation in the basal core promoter (BCP) and have a reduced expression level of HBeAg, in HBV persistence and pathogenesis. In addition, our recent studies indicated that HBV persistence could also be affected by the size of viral inoculums and interferons ¿ and ¿ (IFN-¿/¿). Thus, we will also investigate the role of these factors in HBV persistence. Our proposed research will provide important information for us to understand HBV replication and persistence and facilitate the development of treatments for HBV patients.