[英语，研究]Hepatitis B Virus Limits Response of Human Hepatocytes to Inter

StephenW

http://www.virushunters.net/showabstract.php?pmid=21376046&source=newsletter&utm_source=Newsletter&utm_medium=text&utm_campaign=Monthly%2BNewsletter
Gastroenterology (2011) 0: .

Hepatitis B Virus Limits Response of Human Hepatocytes to Interferon-α in Chimeric Mice.

M ütgehetmann, T Bornscheuer, T Volz, L Allweiss, JH Bockmann, JM Pollok, AW Lohse, J Petersen, M Dandri

BACKGROUND & AIMS: Interferon (IFN)-α therapy is not effective for most patients with chronic hepatitis B virus (HBV) infection, for unclear reasons. We investigated whether HBV infection reduced IFN-α-mediated induction of antiviral defence mechanisms in human hepatocytes. METHODS: Human hepatocytes were injected into severe combined immune deficient mice (SCID/beige) that expressed transgenic urokinase plasminogen activator under control of the albumin promoter. Some mice were infected with HBV; infected and uninfected mice were given injections of human IFN-α. Changes in viral DNA and expression of human interferon-stimulated genes (ISGs) were measured by real-time PCR, using human-specific primers, and by immunohistochemistry. RESULTS: Median HBV viremia (0.8log) and intrahepatic loads of HBV RNA decreased 3-fold by 8 or 12 h after each injection of IFN-α, but then increased within 24 h. IFN-α activated expression of human ISGs and nuclear translocation of STAT-1 in human hepatocytes that repopulated the livers of uninfected mice. Although baseline levels of human ISGs were slightly increased in HBV-infected mice, compared with uninfected mice, IFN-α failed to increase expression of the ISGs OAS-1, MxA, MyD88, and TAP-1 (which regulates antigen presentation) in HBV-infected mice. Remarkably, IFN-α did not induce nuclear translocation of STAT-1 in HBV-infected human hepatocytes. Administration of the nucleoside analogue entecavir (for 20 days) suppressed HBV replication but did not restore responsiveness to IFN-α. CONCLUSIONS: HBV prevents induction of IFN-α signaling by inhibiting nuclear translocation of STAT-1; this can interfere with transcription of ISGs in human hepatocytes. These effects of HBV might contribute to the limited effectiveness of endogenous and therapeutic IFN-α in patients and promote viral persistence.

StephenW

胃肠病学杂志（2011年）0：。

乙型肝炎病毒的大小人肝细胞干扰素-α嵌合小鼠。

M ütgehetmann，T Bornscheuer，T福尔茨，午Allweiss，Jh的Bockmann，JM波洛克，胡洛斯，强彼得森，男Dandri

背景与目的：干扰素（IFN）-α治疗对大多数患者是慢性乙型肝炎病毒（HBV）的感染原因不明，有效的。我们调查是否感染乙肝病毒减少干扰素-α介导的人肝细胞诱导抗病毒防御机制。方法：人肝细胞注射到重症联合免疫缺陷小鼠（SCID鼠/米色）的转基因表达尿激酶根据白蛋白启动子控制纤溶酶原激活剂。一些小鼠感染了乙肝病毒，感染和未感染小鼠给予人α-干扰素注射。在病毒DNA和人干扰素刺激基因（ISGs）表达的改变是利用实时PCR技术，利用人类特有的引物，通过免疫组化。结果：乙肝病毒血症病毒RNA的中位数（0.8log）和肝内负荷下降了3倍，由8个或12小时后每α-干扰素注射，但随后在24小时增加α-干扰素对人ISGs和STAT - 1在人类肝细胞的核转激活表达式，重新填充未感染小鼠的肝脏。虽然人类ISGs基准水平略有增加，乙肝病毒感染的小鼠，比未感染小鼠，干扰素-α没有增加美洲国家组织的ISGs - 1，MxA，MyD88的，和TAP - 1的表达（即调节抗原提呈）在HBV感染小鼠。值得注意的是，干扰素-α诱导的核没有乙肝病毒感染的人肝细胞的STAT - 1易位。总局的核苷类似物恩替卡韦（20天）抑制乙肝病毒复制，但没有恢复的响应干扰素-α。结论：乙肝病毒可以防止α-干扰素通过抑制的STAT - 1核易位信号​​感应，这可能会干扰在人类肝细胞ISGs转录。乙肝病毒可能是造成这些影响的内源性和治疗α-干扰素在有限的病人的有效性和促进病毒的持久性。