For best viewing of the website please use Mozilla Firefox or Google Chrome.

2008年23卷2期

|     

Review

Molecular Therapy and Prevention of Liver Diseases

Hubert E. Blum

2008, 23(2): 81 doi: 10.1007/s12250-008-2953-8

Molecular analyses have become an integral part of biomedical research as well as clinical medicine. The definition of the genetic basis of many human diseases has led to a better understanding of their pathogenesis and has in addition offered new perspectives for their diagnosis, therapy and prevention. Genetically, human diseases can be classified as hereditary monogenic, acquired monogenic and polygenic diseases. Based on this classification, gene therapy is based on six concepts: (1) gene repair, (2) gene substitution, (3) cell therapy, (4) block of gene expression or function, (5) DNA vaccination and (6) gene augmentation. While major advances have been made in all areas of gene therapy during the last years, various delivery, targeting and safety issues need to be addressed before these strategies will enter clinical practice. Nevertheless, gene therapy will eventually become part of the management of patients with various liver diseases, complementing or replacing existing therapeutic and preventive strategies.

乙肝病毒DNA整合的研究进展

林菊生, 高琳琳Ju-sheng LIN *

2008, 23(2): 93 doi: 10.1007/s12250-008-2939-6

Since HBV DNA integration was discovered for the first time in 1980, various methods have been used to detect and study it, such as Southern Blot, in situ hybridization, polymerase chain reaction and so on. HBV DNA integration is thought to be random on the whole although some hot spots of integration were described by some researchers, one of which might be the repetitive sequences of the genomic DNA. Besides, DNA damage, especially double-strand breaks could promote HBV DNA integration into host genome. HBV DNA integration into cells may damage the stability of the genome, cause DNA rearrangement, promote DNA deletion and induce the formation of HCC.

自从1980年首次发现乙肝病毒DNA整合,用来研究和检测的方法层出不穷,如Southern 印迹,原位杂交,聚合酶链式反应等。尽管某些科学家发现了一些乙肝病毒DNA的整合热点,如基因组的重复序列,但总体上来说这种整合是随机的。另外,DNA损伤,尤其是双链断裂可以促进乙肝病毒DNA整合入宿主基因。乙肝病毒DNA整合入宿主细胞可能会影响基因组的稳定性,引起DNA重排,促进DNA缺失并诱发肝细胞癌的形成。

乙型肝炎病毒干扰细胞内的信号传导*

徐飏, 石春薇, 张小勇, 裴荣娟, 陆蒙吉

2008, 23(2): 100 doi: 10.1007/s12250-008-2940-0

乙型肝炎病毒的蛋白能影响细胞内的信号传导,引起细胞基因表达的改变。现有研究结果显示乙肝病毒的核衣壳蛋白和多聚酶蛋白的氨基末端片段(TP)能抑制干扰素的信号传导。此外,在肝癌细胞系中,乙肝病毒的复制和乙肝蛋白的表达能引起细胞基因表达的全局性改变。乙肝病毒的复制会引起细胞内干扰素刺激基因(ISGs)表达的异常调控,使用抗乙肝病毒的药物抑制病毒复制能部分恢复细胞内ISGs的表达调控。乙肝病毒的多聚酶末端蛋白(TP)能调节ISGs的表达,并能增强乙肝病毒的复制。乙肝病毒对细胞内信号传导的干扰调节作用在乙肝病毒的致病机制中可能占有重要地位。

Recent Advances in Research on Hepadnaviral Infection in the Woodchuck Model*

Ina Schulte, juan ZHANG, ji MENG, juan PEI, Mengji LU, Michael Roggendorf

2008, 23(2): 107 doi: 10.1007/s12250-008-2941-z

The woodchuck model is an excellent animal model to study hepadnaviral infection. The new progresses in this model made possible to examine the T-cell mediated immune responses in acute and chronic hepadnaviral infection. Recently, a new assay for cytotoxic T-cells based on detection of CD107 was established for the woodchuck model. In addition, new immunotherapeutic approaches based on combination of potent antiviral treatment and DNA-protein vaccines were proven to be useful for treatment of chronic hepatitis B.

The Role of the Innate Immune System of the Liver in the Control of HBV and HCV*

Jun Wu, Ruth Br?ring, J?rg F. Schlaak*

2008, 23(2): 116 doi: 10.1007/s12250-008-2942-y

Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infection are among the most frequent causes of chronic liver disease worldwide. As recent studies suggested that Toll like receptor (TLR)-based therapies may represent a promising approach in the treatment of HBV infection, we have studied the role of the local innate immune system of the liver as possible mediator of this effect. Murine non-parenchymal liver cells (NPC; Kupffer cells, KC; sinusoidal endothelial cells, LSEC) were isolated from C57/BL6 and stimulated by TLR 1-9 agonists. Supernatants were harvested and assayed for their antiviral activity against HBV in HBV-Met cells and HCV in the murine HCV replicon cell line MH1. Only supernatants from TLR 3 and -4 stimulated KC and TLR 3 stimulated LSEC were able to potently suppress HBV and HCV replication. By using neutralizing antibodies we could demonstrate that the TLR 3- but not the TLR 4 mediated effect is exclusively mediated through IFN-β. Our data indicate that TLR 3 and -4 mediated stimulation of NPC leads to production of IFN-β which can potently suppress HBV and HCV replication. This is of relevance for the local control of viral hepatitis infection by the innate immune system of the liver, the development of novel TLR-based therapeutic approaches and sheds new light on the viral crosstalk between HCV (TLR 3 stimulator) and HBV.

Virus-host Interactions during Hepatitis C Virus Entry - Implications for Pathogenesis and Novel Treatment Approaches

Joachim Lupberger, Mirjam B, Anita Haberstroh, Eva K, Sophie Krieger, Eric Soulier, Christine Thumann, Cathy Royer, Samira Fafi-Kremer, Catherine Schuster, oise Stoll-Keller, Hubert E, and Thomas

2008, 23(2): 124 doi: 10.1007/s12250-008-2943-x

Hepatitis C virus (HCV) is a member of the Flaviviridae family and causes acute and chronic hepatitis. Chronic HCV infection may result in severe liver damage including liver cirrhosis and hepatocellular carcinoma. The liver is the primary target organ of HCV, and the hepatocyte is its primary target cell. Attachment of the virus to the cell surface followed by viral entry is the first step in a cascade of interactions between the virus and the target cell that is required for successful entry into the cell and initiation of infection. This step is an important determinant of tissue tropism and pathogenesis; it thus represents a major target for antiviral host cell responses, such as antibody-mediated virus neutralization. Following the development of novel cell culture models for HCV infection our understanding of the HCV entry process and mechanisms of virus neutralization has been markedly advanced. In this review we summarize recent developments in the molecular biology of viral entry and its impact on pathogenesis of HCV infection, development of novel preventive and therapeutic antiviral strategies.

The Role of Viral Mutation in the Pathogenesis of Chronic Viral Hepatitis

Yu-ming WANG *, Lin LIU

2008, 23(2): 132 doi: 10.1007/s12250-008-2944-9

乙型、丙型肝炎病毒的准种特性在慢性乙、丙型肝炎的发病机制、免疫逃避及药物耐受等过程中都有重要作用。目前对丙型肝炎尚缺乏有效的治疗。一系列核苷类似物(NA)的推出给乙型肝炎的治疗带来了契机,然而耐药毒株在治疗过程中可逐渐累积,并逐渐成为优势毒株,导致病毒种群整体对药物的耐受。换用其它敏感核苷类似物又可抑制这些耐药变异株。因此,理解药物压力下病毒准种的演变对制定抗病毒策略、监测抗病毒过程有至关重要的意义。免疫应答与逃逸是复杂的过程,宿主和病毒因素在此过程中都有重要作用。进一步理解宿主和病毒的相互作用和关系对预防、诊断和治疗策略的优化有重要意义。

临床及临床前抗乙肝药物的研究

王桂凤, 左建平,

2008, 23(2): 137 doi: 10.1007/s12250-008-2945-8

到2007年为止,治疗乙肝的药物主要分为两种:干扰素和核苷类似物。然而,由于α-干扰素的副作用及乙肝病毒对核苷类抑制剂的作用早期形成了相当的耐药性,导致其临床治疗受到了限制,所以需要新型结构和作用机制药物的出现。本文对已被FDA批准治疗乙肝病毒感染,处于临床实验以及临床前研究的一些代表性化合物进行了综述,并探讨了抗慢性乙肝病毒感染的潜在靶点和策略。

乙肝病毒X蛋白与细胞因子相互作用在肿瘤发生发展中的生物学效应

王适群, 吴建国

2008, 23(2): 146 doi: 10.1007/s12250-008-2952-9

乙肝病毒X蛋白作为一种间接的反式转录活化因子能调控许多细胞与病毒基因,在致病和肝细胞癌的发生发展中起着重要的作用。我们在本文中重点描述了乙肝病毒X蛋白与4种重要细胞因子相互作用的生物学效应,包括炎症因子(COX-2和iNOS),肿瘤蛋白(Ras)以及新分离鉴定的肿瘤抑制因子(YueF)。同时探讨了细胞因子的特性及其在肝细胞癌发生发展中的作用。