HBV replication and persistence in mouse models

描述（由申请人提供）： B型肝炎病毒（HBV）是一种嗜肝病毒，可引起严重的肝脏疾病，包括急性和慢性肝炎以及肝细胞癌（HCC）。世界上约有3.5亿人慢性感染这种病毒，每年导致50万至100万人死亡。HBV的宿主范围非常狭窄，这极大地阻碍了其研究。然而，近年来几种小鼠模型的发展已经部分克服了这个问题，并为理解HBV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HBV转基因小鼠与雄性幼稚小鼠杂交，我们能够获得非转基因小鼠幼崽。当这些非转基因小鼠幼崽通过流体动力学注射注射HBV基因组DNA时，HBV复制在小鼠肝脏中持续长达7个月，类似于HBV在患者中的垂直传播。在临床上，超过90%的婴儿出生的妇女谁是HBV携带者将成为HBV携带者。这种“垂直传播”是HBV传播的最常见方式，特别是在HBV流行区，也是慢性HBV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HBV持续存在的机制。我们将使用这种小鼠模型来研究HBV e抗原（HBeAg）的作用，这被认为是在建立持续感染后的垂直传播，和一类HBV突变体，其中携带一个双核苷酸突变的基础核心启动子（BCP）和HBeAg的表达水平降低，在HBV的持久性和发病机制中发挥了非常重要的作用。此外，我们最近的研究表明，HBV的持久性也可能受到病毒接种量和干扰素（IFN-<$/<$）的影响。因此，我们也将研究这些因素在HBV持续性中的作用。我们的研究将为我们了解HBV的复制和持续性提供重要信息，并促进HBV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.