Hepatitis B virus e antigen in viral persistence

摘要 乙肝病毒是人类最重要的病原体之一。大约有3亿人 全球慢性乙肝病毒携带者，每年造成近100万人死亡。大多数慢性乙肝病毒携带者 在生命早期从受感染的母亲那里感染了病毒。乙肝病毒的宿主范围非常窄，这在很大程度上 阻碍了它的研究。通过与携带1.3聚体超长的雌性半合子转基因小鼠杂交 为了研究乙肝病毒基因组对雄性幼稚小鼠的影响，我们建立了一种小鼠模型来研究病毒持续存在的机制。 我们发现，乙肝病毒在小鼠体内的持久性依赖于HBVe抗原(HBeAg)和Kupffer细胞， 驻留在肝脏的巨噬细胞。HBeAg对乙肝病毒持久性的要求与 婴儿乙肝病毒持续存在与母亲HBeAg阳性有关的临床观察 我们最近的研究揭示了HBeAg和肝巨噬细胞之间有趣的相互作用。这种相互作用 既可以促进乙肝病毒的持续存在，也可以促进乙肝病毒的清除。在本申请中，我们将继续研究这一点 HBeAg和巨噬细胞之间的相互作用以了解乙肝病毒持续存在的机制。我们最近有过 发现HBeAg可以重新编程巨噬细胞的新陈代谢以促进氧化 磷酸化(OXPHOS)。HBeAg的这种代谢重新编程似乎对 库普弗细胞的促炎活性减弱。因此，我们将继续研究HBeAg如何 巨噬细胞代谢重编及其在抗乙肝治疗中的意义 回应。我们的初步结果还表明，Toll样受体4(TLR4)介导了HBeAg的作用 在库普弗细胞上。因此，我们还将研究TLR4是否作为HBeAg的受体，以及它在 乙肝病毒的持久性。最后，我们将确定HBeAg本身是否足以促进乙肝病毒的持续存在 以及HBeAg能否在子宫内培养Kupffer细胞以促进HBV持久化。我们建议的研究将 为我们了解乙肝病毒持续存在的机制提供了重要信息，并有助于改善 慢性乙肝患者的治疗。

Abstract Hepatitis B virus (HBV) is one of the most important human pathogens. There are approximately 300 million chronic HBV carriers in the world, resulting in nearly 1 million deaths every year. Most chronic HBV carriers acquired the virus from their infected mother early in life. HBV has a very narrow host range, which has greatly hampered its research. By crossing female hemizygous HBV transgenic mice that carry the 1.3mer overlength HBV genome to male naïve mice, we had developed a mouse model to study the mechanism of HBV persistence. We found that the persistence of HBV in mice was dependent on the HBV e antigen (HBeAg) and Kupffer cells, the resident macrophages of the liver. The requirement of HBeAg for HBV persistence is consistent with the clinical observation that the HBV persistence in babies is dependent on the HBeAg-positivity of their mothers. Our recent studies revealed an interesting interplay between HBeAg and hepatic macrophages. This interplay can either promote the HBV persistence or HBV clearance. In this application, we will continue to study this interplay between HBeAg and macrophages to understand the mechanism of HBV persistence. We had recently discovered that HBeAg could reprogram the metabolism of macrophages to promote the oxidative phosphorylation (OXPHOS). This metabolic reprogramming by HBeAg appears to be important for the attenuation of pro-inflammatory activities of Kupffer cells. We will therefore continue to study how HBeAg reprograms the metabolism of macrophages and study the implication of this reprogramming in the anti-HBV response. Our preliminary results also indicated that the toll-like receptor 4 (TLR4) mediated the effects of HBeAg on Kupffer cells. Thus, we will also investigate whether TLR4 serves as the receptor of HBeAg and its role in HBV persistence. Finally, we will determine whether HBeAg by itself is sufficient to promote HBV persistence and whether HBeAg can train Kupffer cells in utero to promote HBV persistence. Our proposed studies will provide important information for us to understand the mechanism of HBV persistence and help to improve the treatments for chronic HBV patients.