[英语研究]HBV Virus Limits Response of Human Hepatocytes to Interfer

StephenW

http://www.gastrojournal.org/article/S0016-5085%2811%2900269-1/abstract
Hepatitis B Virus Limits Response of Human Hepatocytes to Interferon-α in Chimeric MiceBackground & AimsInterferon (IFN)-α therapy is not effective for most patients with chronic hepatitis B virus (HBV) infection for reasons that are not clear. We investigated whether HBV infection reduced IFN-α–mediated induction of antiviral defense mechanisms in human hepatocytes.
MethodsHuman 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 polymerase chain reaction, using human-specific primers, and by immunohistochemistry.
ResultsMedian HBV viremia (0.8log) and intrahepatic loads of HBV RNA decreased 3-fold by 8 or 12 hours after each injection of IFN-α, but increased within 24 hours. IFN-α activated expression of human ISGs and nuclear translocation of signal transducers and activators of transcription–1 (STAT1) 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. IFN-α did not induce nuclear translocation of STAT1 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.
ConclusionsHBV prevents induction of IFN-α signaling by inhibiting nuclear translocation of STAT1; 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.

Keywords: cccDNA, uPA, Antiviral Therapy, Innate Immunity

Abbreviations used in this paper: cccDNA, covalently closed circular DNA, ETV, entecavir, IFN, interferon, ISGs, interferon-stimulated genes, MHC, major histocompatibility complex, MxA, mixovirus resistance protein A, OAS-1, 2′-5′ oligoadenylate synthase 1, PCR, polymerase chain reaction, pgRNA, pregenomic RNA, rcDNA, relaxed circular DNA, SCID, severe combined immune-deficient, STAT, signal transducers and activators of transcription, TLR, Toll-like receptor, uPA, urokinase plasminogen activator

StephenW

背景和目的

干扰素（IFN）-α治疗不适合与慢性乙型肝炎病毒（HBV）的原因尚不清楚感染最有效的治疗。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聚合酶链反应，用人类特异性引物，并通过免疫组化。
结果

乙肝病毒血症中位数（0.8log）和乙肝病毒RNA的肝内负荷减少3 8倍或12小时后，每个α-干扰素注射，但在24小时内增加。 α-干扰素对人ISGs和信号转导和转录核转- 1激活剂（内STAT1）活化表达人肝细胞的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。干扰素-α诱导的核没有乙肝病毒感染的人类肝细胞STAT1的易位。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

乙肝防止α-干扰素通过抑制STAT1的核转信号感应，这会干扰人类肝细胞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。

关键词：cccDNA的，尿激酶，抗病毒治疗，先天免疫

本文中使用的简称：cccDNA的，共价闭合环状DNA，教育电视，恩替卡韦，干扰素，干扰素，ISGs，干扰素刺激基因，MHC，主要组织相容性复合，MxA，mixovirus抵抗蛋白A，美洲国家组织- 1，2' - 5'寡腺苷酸合成酶1，PCR扩增，聚合酶链反应，pgRNA，前基因组RNA的，rcDNA，轻松环状DNA，免疫缺陷，严重联合免疫缺陷，转录，信号转导和转录激活因子，Toll样受体，Toll样受体，尿激酶，尿激酶型纤溶酶原激活物