慢性乙型肝炎患者IFN-α治疗无应答与肝组织基因表达差异关系的初步研究
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摘要
目的:利用基因芯片技术检测慢性乙型肝炎患者α干扰素(IFN-α)治疗应答者(Rs)和无应答者(NRs)之间肝组织的表达基因差异,探讨IFN-α治疗慢乙肝无应答的分子机制。
方法:采用表达谱基因芯片检测IFN-α治疗前患者肝组织的全基因表达情况,筛选出在7例治疗无应答者和6例治疗应答者之间差异表达的基因,对这些差异基因进行Gene Ontology分析和KEGG通路分析,并对部分明显差异表达基因进行实时荧光定量PCR验证。
结果:在NRs和Rs组共筛选出3592个差异表达基因(P <0 .05),而这些差异基因主要集中在干扰素诱导基因(ISGs)和免疫调节相关基因,且ISGs在治疗前的NRs高表达而免疫调节相关基因低表达。其中,处于一条抑制干扰素信号通路的两个ISGs(USP18和CEB1)在NRs高表达,而具有潜在抗病毒活性的ISG20基因在NRs低表达,这可能和IFN-α治疗无应答密切相关。
结论:NRs和Rs在IFN-α治疗前即具有不同的肝脏基因表达谱,在治疗前高表达具有抑制IFN通路的ISGs并抑制免疫反应将预示着治疗无应答,并可望在治疗前成功预测IFN-α治疗效果。
Objective: To screen the differentially expressed genes between responders(Rs) and nonresponders(NRs) in CHB patients treated with IFN-α, and to explore the molecular basis for treatment failure.
Methods: Expression profiling was performed on percutaneous needle liver biopsy specimens taken before therapy.Gene expression levels were compared between 7 NRs and 6 Rs,Gene Ontology category and KEGG pathway were analyzed for differentially expressed genes, and the selected differentially expressed genes were confirmed using real-time polymerase chain reaction.
Results: We identified 3592 genes whose expression levels differed significantly between all Rs and NRs (P <0 .05); many of these genes are IFN stimulated genes(ISGs) and immune related genes.The ISGs are more highly expressed while immune related genes are inhibited in NRs before IFN-αtreatment.Two ISGs(CEB1 and USP18) which are linked in an IFN-inhibitory pathway are highly expressed in NRs, and a potential antiviral gene ISG20 is inhibited in NRs, suggesting a possible rationale for treatment non-response.
Conclusions: NRs and Rs have different liver gene expression profiles before IFN-αtreatment. Preactivation of the IFN signaling pathway leading to the increased expression of inhibitory ISGs and inhibition of immune response in the pretreatment livers were associated with NRs.
方法:采用表达谱基因芯片检测IFN-α治疗前患者肝组织的全基因表达情况,筛选出在7例治疗无应答者和6例治疗应答者之间差异表达的基因,对这些差异基因进行Gene Ontology分析和KEGG通路分析,并对部分明显差异表达基因进行实时荧光定量PCR验证。
结果:在NRs和Rs组共筛选出3592个差异表达基因(P <0 .05),而这些差异基因主要集中在干扰素诱导基因(ISGs)和免疫调节相关基因,且ISGs在治疗前的NRs高表达而免疫调节相关基因低表达。其中,处于一条抑制干扰素信号通路的两个ISGs(USP18和CEB1)在NRs高表达,而具有潜在抗病毒活性的ISG20基因在NRs低表达,这可能和IFN-α治疗无应答密切相关。
结论:NRs和Rs在IFN-α治疗前即具有不同的肝脏基因表达谱,在治疗前高表达具有抑制IFN通路的ISGs并抑制免疫反应将预示着治疗无应答,并可望在治疗前成功预测IFN-α治疗效果。
Objective: To screen the differentially expressed genes between responders(Rs) and nonresponders(NRs) in CHB patients treated with IFN-α, and to explore the molecular basis for treatment failure.
Methods: Expression profiling was performed on percutaneous needle liver biopsy specimens taken before therapy.Gene expression levels were compared between 7 NRs and 6 Rs,Gene Ontology category and KEGG pathway were analyzed for differentially expressed genes, and the selected differentially expressed genes were confirmed using real-time polymerase chain reaction.
Results: We identified 3592 genes whose expression levels differed significantly between all Rs and NRs (P <0 .05); many of these genes are IFN stimulated genes(ISGs) and immune related genes.The ISGs are more highly expressed while immune related genes are inhibited in NRs before IFN-αtreatment.Two ISGs(CEB1 and USP18) which are linked in an IFN-inhibitory pathway are highly expressed in NRs, and a potential antiviral gene ISG20 is inhibited in NRs, suggesting a possible rationale for treatment non-response.
Conclusions: NRs and Rs have different liver gene expression profiles before IFN-αtreatment. Preactivation of the IFN signaling pathway leading to the increased expression of inhibitory ISGs and inhibition of immune response in the pretreatment livers were associated with NRs.
引文
[1] Safioleas M, Lygidakis NJ, Manti C. Hepatitis B today [J].Hepatogastroenterology 2007;54(74):545-548.
[2] Yang YF, Zhao W, Xia HM, et al. Long-term efficacy of interferon alpha therapy on hepatitis B viral replication in patients with chronic hepatitis B:a meta-analysis [J]. Antiviral Res 2010;85(2):361-365.
[3] Christen V, Duong F, Bernsmeier C, Sun D, Nassal M, Heim MH. Inhibition of alpha interferon signaling by hepatitis B virus [J].J Virol 2007;81(1):159-165.
[4] Bonino F, Marcellin P, Lau GK, et al. Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B [J]. Gut 2007;56(5):699-705.
[5] Tangkijvanich P, Komolmit P, Mahachai V, et al. Comparison between quantitative hepatitis B surface antigen, hepatitis B e-antigen and hepatitis B virus DNA levels for predicting virological response to pegylated interferon-alpha-2b therapy in hepatitis B e-antigen-positive chronic hepatitis B [J]. Hepatol Res 2010;40(4):269-277.
[6] Sun WJ, Qin Bo. The Study Progress in the mechanisms of chronic hepatitis B patients no response with interfeon alpha treatment [J]. Zhonghua Nei Ke Za Zhi 2009;48(3):250-252.(in chinese)
[7] Buster EH, Hansen BE, Lau GK, et al. Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa [J]. Gastroenterology 2009;137(6):2002-2009.
[8] Han YN, Yang JL, Zheng SG,Tang Q, Zhu W.Relationship of human leukocyte antigen class II genes with the susceptibility to hepatitis B virus infection and the response to interferon in HBV-infected patients [J]. World J Gastroenterol 2005; 11(36): 5721-5724.
[9] Gong QM, Kong XF, Yang ZT, et al. Association study of IFNΑR2 and IL10RB genes with the susceptibility and interferon response in HBV infection [J]. J Viral Hepat 2009;16(9):674-680.
[10] Hayashi K, Katano Y, Honda T, et al. Mutations in the interferon sensitivity- determining region of hepatitis C virus genotype 2a correlate with response to pegylated-interferon-alpha 2a monotherapy [J]. J Med Virol 2009;81(3):459-466.
[11] Wang X, Yuan ZH, Zheng LJ, et al. Gene expression profiles in an hepatitis B virus transfected hepatoblastoma cell line and differentially regulated gene expression by interferon-α[J]. World J Gastroenterol 2004; 10(12): 1740-1745.
[12] Xiong W, Wang X, Liu XY, et al. Analysis of gene expression in hepatitis B virus transfected cell line induced by interferon [J]. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao 2003; 35(12): 1053-1060. (in chinese)
[13] Chen PJ, Lin CG, Lin FY, Chen E, Wu LS. Genetic structural differences between responders and non-responders to interferon therapy for chronic hepatitis-B patients [J].J Hum Genet 2006;51(11):984-991.
[14] Chen L, Borozan I, Feld J, et al. Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection [J]. Gastroenterology 2005; 128(5): 1437-1444.
[15] Randall G,Chen L,Panis M, et al.Silencing of USP18 potentiates the antiviral activity of interferon against hepatitis C virus infection [J]. Gastroenterology 2006;131(5):1584-1591.
[16] Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008;2(3):263-283.
[17] Wright GW, Simon RM. A random variance model for detection of differential gene expression in small microarray experiments [J]. Bioinformatics 2003; 19(18): 2448-2455.
[18] Eisen MB, Spellman PT, Brown PO, Botstein D. Cluster analysis and display of genome-wide expression patterns [J].Proc Natl Acad Sci U S A 1998;95(25):14863-8.
[19] Ji X, Cheung R, Cooper S, et al. Interferon alfa regulated gene expression in patients initiating interferon treatment for chronic hepatitis C [J]. Hepatology 2003;37(3):610-621.
[20] Asselah T, Bieche I, Narguet S, et al. Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C [J]. Gut 2008;57(4):516-524.
[21] Feld JJ, Nanda S, Huang Y, et al. Hepatic gene expression during treatment with peginterferon and ribavirin: identifying molecular pathways for treatment response [J]. Hepatology 2007;46(5):1548-1563.
[22] Malakhova OA, Yan M, Malakhov MP, et al. Protein ISGylation modulates theJAK-STAT signaling pathway [J]. Genes Dev 2003;17(4):455–460.
[23] Knobeloch KP, Uterm?hlen O, Kisser A, Prinz M, Horak I. Reexamination of the role of ubiquitin-like modifier ISG15 in the phenotype of UBP43-deficient mice [J]. Mol Cell Biol 2005; 25(24):11030–11034.
[24] Osiak A, Uterm?hlen O, Niendorf S, Horak I, Knobeloch KP. ISG15, an interferon-stimulated ubiquitin-like protein, is not essential for STAT1 signaling and responses against vesicular stomatitis and lymphocytic choriomeningitis virus [J]. Mol Cell Biol 2005;25(15):6338–6345.
[25] Malakhova OA, Kim KI, Luo JK, et al. UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity [J]. EMBO J 2006; 25(11): 2358-2367.
[26] Kim KI, Yan M, Malakhova O, et al. Ube1L and protein ISGylation are not essential for alpha/beta interferon signaling [J]. Mol Cell Biol 2006;26(2):472-479.
[27] Kim JH, Luo JK, Zhang DE. The Level of hepatitis B virus replication is not affected by protein ISG15 modification but is reduced by inhibition of UBP43 (USP18) expression [J]. J Immunol 2008;181(9):6467-6472.
[28] Zhou A, Paranjape JM, Der SD, Williams BR, Silverman RH. Interferon action in triply deficient mice reveals the existence of alternative antiviral pathways [J]. Virology 1999;258(2):435-440.
[29] Presti RM, Popkin DL, Connick M, Paetzold S, Virgin HW 4th. Novel cell type–specific antiviral mechanism of interferon gamma action in macrophages [J].J Exp Med 2001; 193(4): 483–496.
[30] Rang A, Bruns M, Heise T, Will H. Antiviral activity of interferon-alpha against hepatitis B virus can be studied in non-hepatic cells and is independent of MxA [J]. J Biol Chem 2002;277(10):7645-7647.
[31] Chang JH, Kato N,Muroyama R, et al.Double-stranded RNA-activated protein kinase inhibits hepatitis C virus replication but may be not essential in interferon treatment [J]. Liver Int 2010;30(2):311-318.
[32] Guidotti LG, Morris A, Mendez H, et al. Interferon-regulated pathways that control hepatitis B virus replication in transgenic mice [J]. J Virol 2002; 76(6): 2617-2621.
[33] Kanazawa N, Kurosaki M, Sakamoto N et al. Regulation of hepatitis C virus replication by interferon regulatory factor 1 [J]. J Virol 2004;78(18):9713-9720.
[34] Itsui Y, Sakamoto N, Kakinuma S, et al. Antiviral effects of the interferon-inducedprotein guanylate binding protein 1 and its interaction with the hepatitis C virus NS5B protein [J]. Hepatology 2009;50(6):1727-1737.
[35] Itsui Y, Sakamoto N, Kurosaki M, et al. Expressional screening of interferon-stimulated genes for antiviral activity against hepatitis C virus replication [J]. J Viral Hepat 2006;13(10):690-700.
[36] Nguyen LH, Espert L, Mechti N, Wilson DM 3rd.The human interferon- and estrogen-regulated ISG20/HEM45 gene product degrades single-stranded RNA and DNA in vitro [J].Biochemistry 2001;40(24):7174-7179.
[37] Espert L, Degols G, Gongora C, et al. ISG20, a new interferon-induced RNase specific for single-stranded RNA, defines an alternative antiviral pathway against RNA genomic viruses [J]. J Biol Chem 2003;278(18):16151-16158.
[38] Wieland S, Thimme R, Purcell R H, Chisari FV. Genomic analysis of the host response to hepatitis B virus infection [J]. Proc Natl Acad Sci U S A 2004; 101(17): 6669-6674.
[39] HAO Y,Yang D. Cloning, eukaryotic expression of human ISG20 and preliminary study on the effect of its anti-HBV [J]. J Huazhong Univ Sci Technolog Med Sci 2008;28(1):11-13.
[1] Janssen HL, van Zonneveld M, Senturk H,et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial [J]. Lancet,2005,365(9454):123-129.
[2] Feuerstadt P, Bunim AL, Garcia H,et al.Effectiveness of Hepatitis C Treatment with Pegylated Interferon and Ribavirin in Urban Minority Patients [J]. Hepatology,2010,51(4):1137-1143.
[3] Giannini EG, Basso M, Savarino V, et al. Predictive factors for response topeginterferon-alpha and ribavirin treatment of chronic HCV infection in patients aged 65 years and more [J].Dig Dis Sci,2010,55(11):3193-3199. Epub 2010 Sep 18.
[4] Moreau I, Levis J, Crosbie O, et al.Correlation between pre-treatment quasispecies complexity and treatment outcome in chronic HCV genotype 3a [J].Virol J,2008,5(9):78.
[5] Wang Y,Wei L, Jiang D,et al. In vitro resistance to interferon of hepatitis B virus with precore mutation [J].World J Gastroenterol,2005,11(5):649-655.
[6] Erhardt A, Reineke U, Blondin D, Mutations of the core promoter and response to interferon treatment in chronic replicative hepatitis B [J]. Hepatology, 2000, 31(3): 716-725.
[7] Tangkijvanich P, Komolmit P, Mahachai V, et al. Low pretreatment serum HBsAg level and viral mutations as predictors of response to PEG-interferon alpha-2b therapy in chronic hepatitis B [J].J Clin Virol,2009,46(2):117-123.
[8] Nakagawa M, Sakamoto N, Ueyama M, et al. Mutations in the interferon sensitivity determining region and virological response to combination therapy with pegylated-interferon alpha 2b plus ribavirin in patients with chronic hepatitis C-1b infection [J]. J Gastroenterol,2010,45(6):656-665.
[9] Torres-Puente M, Cuevas JM, Jimenez-Hernandez N, et al. Hepatitis C virus and the controversial role of the interferon sensitivity determining region in the response to interferon treatment [J]. J Med Virol 2008;80(2): 247–253.
[10] Munoz de Rueda P, Casado J, Paton R, et al. Mutations in E2-PePHD, NS5A-PKRBD, NS5A-ISDR, and NS5A-V3 of hepatitis C virus genotype 1 and their relationships to pegylated interferon-ribavirin treatment responses [J]. J Virol,2008,82(13): 6644–6653.
[11] Berg T, Mas Marques A, Hohne M, et al. Mutations in the E2-PePHD and NS5A region of hepatitis C virus type 1 and the dynamics of hepatitis C viremia decline during interferon alfa treatment [J].Hepatology,2000,32(6):1386–1395.
[12] Seo Y, Yoon S, Hamano K, et al. Response to interferon-alpha in chronic hepatitis B with and without precore mutant strain detected by mutation site-specific assay [J].J Clin Gastroenterol. 2004,38(5):460-464.
[13] Taylor MW, Grosse WM, Schaley JE, et al. Global effect of PEG-IFN-alpha and ribavirin on gene expression in PBMC in vitro [J].J Interferon Cytokine Res,2004,24(2):107-18.
[14] Chen PJ, Lin CG, Lin FY, et al.Genetic structural differences between responders and non-responders to interferon therapy for chronic hepatitis-B patients [J].J Hum Genet,2006,51(11):984-991
[15] Wang X, Yuan ZH, Zheng LJ, et al. Gene expression profiles in an hepatitis B virus transfected hepatoblastoma cell line and differentially regulated gene expression by interferon-α[J]. World J Gastroenterol, 2004, 10(12):1740-1745.
[16]熊炜,王迅,刘晓颖,等.基因芯片分析干扰素对乙型肝炎病毒转染细胞基因表达的影响[J].生物化学与生物物理学报,2003,35(12):1053-1060.
[17] Wieland SF, Vega RG, Müller R, et al. Searching for interferon-induced genes that inhibit hepatitis B virus replication in transgenic mouse hepatocytes [J]. J Virol,2003, 77(2):1227-1236.
[18] Chen L, Borozan I, Feld J, et al. Hepatic gene expression discriminates respond- ers and nonresponders in treatment of chronic hepatitis C viral infection [J].Gastroenterology, 2005,128(5):1437-1444.
[19] Asselah T,Bieche I,Narguet S,et al.Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C [J].Gut,2008,57(4):516-524
[20] Honda M, Sakai A, Yamashita T,et al. Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C [J]. Gastroenterology,2010,139(2):499-509
[21] Feld JJ, Nanda S, Huang Y, et al.Hepatic gene expression during treatment with peginterferon and ribavirin: identifying molecular pathways for treatment response [J]. Hepatology, 2007, 46(5): 1548-1563.
[22] Randall G,Chen L, Panis M, et al.Silencing of USP18 Potentiates the Antiviral Activity of Interferon Against Hepatitis C Virus Infection [J]. Gastroenterology, 2006, 131(5):1584-1591.
[23]奚敏,臧国庆,冯明亮,等.慢性乙型肝炎干扰素疗效与人类白细胞抗原-等位基因的关系[J].中华传染病杂志,2004,22(4):242-245.
[24] Han YN, Yang JL, Zheng SG, et al. Relationship of human leukocyte antigen class II genes with the susceptibility to hepatitis B virus infection and the response to interferon in HBV-infected patients [J].World J Gastroenterol, 2005,11 (36): 5721-5724
[25]焦健,王江滨.丙型肝炎病毒基因型及患者人类白细胞抗原对其抗病素疗效的影响[J].中华肝脏病杂志,2003,11(10):620-622.
[26] Tan.H., J. Derrick, J. Hong, et al. Global transcriptional profiling combination of type I and type II demonstrates the interferon enhances antiviral and immune responses at clinically relevant doses [J]. J Interferon Cytokine Res,2005,25(10):632–649.
[27] Knapp S, Yee LJ, Frodsham AJ,et al. Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR [J].Genes Immun,2003 ,4(6):411-9.
[28] King JK,Yeh SH,Lin MW,et al.Genetic polymorphisms in interferon pathway and response to interferon treatment in hepatitis B patients:A pilot study [J]. Hepatology, 2002,36(6):1416-1424.
[29] Hijikata M, Mishiro S, Miyamoto C, Furuichi Y, Hashimoto M, Ohta Y. Genetic polymorphism of the MxA gene promoter and interferon responsiveness of hepatitis C patients: revisited by analyzing two SNP sites (-123 and -88) in vivo and in vitro [J]. Intervirology, 2001,44(6):379-382.
[30] Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance [J]. Nature,2009,461(7262): 399-401.
[31] Rauch A, Kutalik Z, Descombes P, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure :a genome-wide association study [J]. Gastroenterology,2010,138(4): 1338–1345.
[32] Mangia A, Thompson AJ, Santoro R et al. An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2 or 3 patients who do not achieve a rapid virologic response [J]. Gastroenterology,2010,139:821-827.
[33] Moons K, Altman D, Vergouwe Y, et al. Prognosis and prognostic research: application and impact of prognostic models in clinical practice [J]. BMJ,2009,338:b606.
[34] Aparicio E, Parera M, Franco S,et al. IL28B SNP rs8099917 Is Strongly Associated with Pegylated Interferon-αand Ribavirin Therapy Treatment Failure in HCV/HIV-1 Coinfected Patients [J]. PLoS One, 2010, 5(10):e13771.
[35] Urban TJ, Thompson AJ, Bradrick SS,et al. IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C [J]. Hepatology, 2010, 52(6):1888-96. doi: 10.1002/hep.23912.Epub 2010 Oct 7
[36] Honda M, Sakai A, Yamashita T,et al.Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C [J]. Gastroenterology,2010,139(2):499-509
[37]黄雁翔,马丽娜,陈新月,等.粘病毒抵抗蛋白A和真核细胞起始因子2α调节区2基因多态性与慢性乙型肝炎干扰素治疗效果的相关性[J].中华肝脏病杂志.2007,15(3):187-191
[38] Tsukada H, Ochi H, Maekawa T, et al. A polymorphism in MAPKAPK3 affects response to interferon therapy for chronic hepatitis C [J]. Gastroenterology, 2009, 136(5):1796-805.
[39] Chambers TJ, Fan X, Droll DA, et al. Quasispecies Heterogeneity within the E1/E2 Region as a Pretreatment Variable during Pegylated Interferon Therapy of Chronic Hepatitis C Virus Infection [J].J Virol,2005,79(5):3071–3083.
[2] Yang YF, Zhao W, Xia HM, et al. Long-term efficacy of interferon alpha therapy on hepatitis B viral replication in patients with chronic hepatitis B:a meta-analysis [J]. Antiviral Res 2010;85(2):361-365.
[3] Christen V, Duong F, Bernsmeier C, Sun D, Nassal M, Heim MH. Inhibition of alpha interferon signaling by hepatitis B virus [J].J Virol 2007;81(1):159-165.
[4] Bonino F, Marcellin P, Lau GK, et al. Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B [J]. Gut 2007;56(5):699-705.
[5] Tangkijvanich P, Komolmit P, Mahachai V, et al. Comparison between quantitative hepatitis B surface antigen, hepatitis B e-antigen and hepatitis B virus DNA levels for predicting virological response to pegylated interferon-alpha-2b therapy in hepatitis B e-antigen-positive chronic hepatitis B [J]. Hepatol Res 2010;40(4):269-277.
[6] Sun WJ, Qin Bo. The Study Progress in the mechanisms of chronic hepatitis B patients no response with interfeon alpha treatment [J]. Zhonghua Nei Ke Za Zhi 2009;48(3):250-252.(in chinese)
[7] Buster EH, Hansen BE, Lau GK, et al. Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa [J]. Gastroenterology 2009;137(6):2002-2009.
[8] Han YN, Yang JL, Zheng SG,Tang Q, Zhu W.Relationship of human leukocyte antigen class II genes with the susceptibility to hepatitis B virus infection and the response to interferon in HBV-infected patients [J]. World J Gastroenterol 2005; 11(36): 5721-5724.
[9] Gong QM, Kong XF, Yang ZT, et al. Association study of IFNΑR2 and IL10RB genes with the susceptibility and interferon response in HBV infection [J]. J Viral Hepat 2009;16(9):674-680.
[10] Hayashi K, Katano Y, Honda T, et al. Mutations in the interferon sensitivity- determining region of hepatitis C virus genotype 2a correlate with response to pegylated-interferon-alpha 2a monotherapy [J]. J Med Virol 2009;81(3):459-466.
[11] Wang X, Yuan ZH, Zheng LJ, et al. Gene expression profiles in an hepatitis B virus transfected hepatoblastoma cell line and differentially regulated gene expression by interferon-α[J]. World J Gastroenterol 2004; 10(12): 1740-1745.
[12] Xiong W, Wang X, Liu XY, et al. Analysis of gene expression in hepatitis B virus transfected cell line induced by interferon [J]. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao 2003; 35(12): 1053-1060. (in chinese)
[13] Chen PJ, Lin CG, Lin FY, Chen E, Wu LS. Genetic structural differences between responders and non-responders to interferon therapy for chronic hepatitis-B patients [J].J Hum Genet 2006;51(11):984-991.
[14] Chen L, Borozan I, Feld J, et al. Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection [J]. Gastroenterology 2005; 128(5): 1437-1444.
[15] Randall G,Chen L,Panis M, et al.Silencing of USP18 potentiates the antiviral activity of interferon against hepatitis C virus infection [J]. Gastroenterology 2006;131(5):1584-1591.
[16] Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008;2(3):263-283.
[17] Wright GW, Simon RM. A random variance model for detection of differential gene expression in small microarray experiments [J]. Bioinformatics 2003; 19(18): 2448-2455.
[18] Eisen MB, Spellman PT, Brown PO, Botstein D. Cluster analysis and display of genome-wide expression patterns [J].Proc Natl Acad Sci U S A 1998;95(25):14863-8.
[19] Ji X, Cheung R, Cooper S, et al. Interferon alfa regulated gene expression in patients initiating interferon treatment for chronic hepatitis C [J]. Hepatology 2003;37(3):610-621.
[20] Asselah T, Bieche I, Narguet S, et al. Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C [J]. Gut 2008;57(4):516-524.
[21] Feld JJ, Nanda S, Huang Y, et al. Hepatic gene expression during treatment with peginterferon and ribavirin: identifying molecular pathways for treatment response [J]. Hepatology 2007;46(5):1548-1563.
[22] Malakhova OA, Yan M, Malakhov MP, et al. Protein ISGylation modulates theJAK-STAT signaling pathway [J]. Genes Dev 2003;17(4):455–460.
[23] Knobeloch KP, Uterm?hlen O, Kisser A, Prinz M, Horak I. Reexamination of the role of ubiquitin-like modifier ISG15 in the phenotype of UBP43-deficient mice [J]. Mol Cell Biol 2005; 25(24):11030–11034.
[24] Osiak A, Uterm?hlen O, Niendorf S, Horak I, Knobeloch KP. ISG15, an interferon-stimulated ubiquitin-like protein, is not essential for STAT1 signaling and responses against vesicular stomatitis and lymphocytic choriomeningitis virus [J]. Mol Cell Biol 2005;25(15):6338–6345.
[25] Malakhova OA, Kim KI, Luo JK, et al. UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity [J]. EMBO J 2006; 25(11): 2358-2367.
[26] Kim KI, Yan M, Malakhova O, et al. Ube1L and protein ISGylation are not essential for alpha/beta interferon signaling [J]. Mol Cell Biol 2006;26(2):472-479.
[27] Kim JH, Luo JK, Zhang DE. The Level of hepatitis B virus replication is not affected by protein ISG15 modification but is reduced by inhibition of UBP43 (USP18) expression [J]. J Immunol 2008;181(9):6467-6472.
[28] Zhou A, Paranjape JM, Der SD, Williams BR, Silverman RH. Interferon action in triply deficient mice reveals the existence of alternative antiviral pathways [J]. Virology 1999;258(2):435-440.
[29] Presti RM, Popkin DL, Connick M, Paetzold S, Virgin HW 4th. Novel cell type–specific antiviral mechanism of interferon gamma action in macrophages [J].J Exp Med 2001; 193(4): 483–496.
[30] Rang A, Bruns M, Heise T, Will H. Antiviral activity of interferon-alpha against hepatitis B virus can be studied in non-hepatic cells and is independent of MxA [J]. J Biol Chem 2002;277(10):7645-7647.
[31] Chang JH, Kato N,Muroyama R, et al.Double-stranded RNA-activated protein kinase inhibits hepatitis C virus replication but may be not essential in interferon treatment [J]. Liver Int 2010;30(2):311-318.
[32] Guidotti LG, Morris A, Mendez H, et al. Interferon-regulated pathways that control hepatitis B virus replication in transgenic mice [J]. J Virol 2002; 76(6): 2617-2621.
[33] Kanazawa N, Kurosaki M, Sakamoto N et al. Regulation of hepatitis C virus replication by interferon regulatory factor 1 [J]. J Virol 2004;78(18):9713-9720.
[34] Itsui Y, Sakamoto N, Kakinuma S, et al. Antiviral effects of the interferon-inducedprotein guanylate binding protein 1 and its interaction with the hepatitis C virus NS5B protein [J]. Hepatology 2009;50(6):1727-1737.
[35] Itsui Y, Sakamoto N, Kurosaki M, et al. Expressional screening of interferon-stimulated genes for antiviral activity against hepatitis C virus replication [J]. J Viral Hepat 2006;13(10):690-700.
[36] Nguyen LH, Espert L, Mechti N, Wilson DM 3rd.The human interferon- and estrogen-regulated ISG20/HEM45 gene product degrades single-stranded RNA and DNA in vitro [J].Biochemistry 2001;40(24):7174-7179.
[37] Espert L, Degols G, Gongora C, et al. ISG20, a new interferon-induced RNase specific for single-stranded RNA, defines an alternative antiviral pathway against RNA genomic viruses [J]. J Biol Chem 2003;278(18):16151-16158.
[38] Wieland S, Thimme R, Purcell R H, Chisari FV. Genomic analysis of the host response to hepatitis B virus infection [J]. Proc Natl Acad Sci U S A 2004; 101(17): 6669-6674.
[39] HAO Y,Yang D. Cloning, eukaryotic expression of human ISG20 and preliminary study on the effect of its anti-HBV [J]. J Huazhong Univ Sci Technolog Med Sci 2008;28(1):11-13.
[1] Janssen HL, van Zonneveld M, Senturk H,et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial [J]. Lancet,2005,365(9454):123-129.
[2] Feuerstadt P, Bunim AL, Garcia H,et al.Effectiveness of Hepatitis C Treatment with Pegylated Interferon and Ribavirin in Urban Minority Patients [J]. Hepatology,2010,51(4):1137-1143.
[3] Giannini EG, Basso M, Savarino V, et al. Predictive factors for response topeginterferon-alpha and ribavirin treatment of chronic HCV infection in patients aged 65 years and more [J].Dig Dis Sci,2010,55(11):3193-3199. Epub 2010 Sep 18.
[4] Moreau I, Levis J, Crosbie O, et al.Correlation between pre-treatment quasispecies complexity and treatment outcome in chronic HCV genotype 3a [J].Virol J,2008,5(9):78.
[5] Wang Y,Wei L, Jiang D,et al. In vitro resistance to interferon of hepatitis B virus with precore mutation [J].World J Gastroenterol,2005,11(5):649-655.
[6] Erhardt A, Reineke U, Blondin D, Mutations of the core promoter and response to interferon treatment in chronic replicative hepatitis B [J]. Hepatology, 2000, 31(3): 716-725.
[7] Tangkijvanich P, Komolmit P, Mahachai V, et al. Low pretreatment serum HBsAg level and viral mutations as predictors of response to PEG-interferon alpha-2b therapy in chronic hepatitis B [J].J Clin Virol,2009,46(2):117-123.
[8] Nakagawa M, Sakamoto N, Ueyama M, et al. Mutations in the interferon sensitivity determining region and virological response to combination therapy with pegylated-interferon alpha 2b plus ribavirin in patients with chronic hepatitis C-1b infection [J]. J Gastroenterol,2010,45(6):656-665.
[9] Torres-Puente M, Cuevas JM, Jimenez-Hernandez N, et al. Hepatitis C virus and the controversial role of the interferon sensitivity determining region in the response to interferon treatment [J]. J Med Virol 2008;80(2): 247–253.
[10] Munoz de Rueda P, Casado J, Paton R, et al. Mutations in E2-PePHD, NS5A-PKRBD, NS5A-ISDR, and NS5A-V3 of hepatitis C virus genotype 1 and their relationships to pegylated interferon-ribavirin treatment responses [J]. J Virol,2008,82(13): 6644–6653.
[11] Berg T, Mas Marques A, Hohne M, et al. Mutations in the E2-PePHD and NS5A region of hepatitis C virus type 1 and the dynamics of hepatitis C viremia decline during interferon alfa treatment [J].Hepatology,2000,32(6):1386–1395.
[12] Seo Y, Yoon S, Hamano K, et al. Response to interferon-alpha in chronic hepatitis B with and without precore mutant strain detected by mutation site-specific assay [J].J Clin Gastroenterol. 2004,38(5):460-464.
[13] Taylor MW, Grosse WM, Schaley JE, et al. Global effect of PEG-IFN-alpha and ribavirin on gene expression in PBMC in vitro [J].J Interferon Cytokine Res,2004,24(2):107-18.
[14] Chen PJ, Lin CG, Lin FY, et al.Genetic structural differences between responders and non-responders to interferon therapy for chronic hepatitis-B patients [J].J Hum Genet,2006,51(11):984-991
[15] Wang X, Yuan ZH, Zheng LJ, et al. Gene expression profiles in an hepatitis B virus transfected hepatoblastoma cell line and differentially regulated gene expression by interferon-α[J]. World J Gastroenterol, 2004, 10(12):1740-1745.
[16]熊炜,王迅,刘晓颖,等.基因芯片分析干扰素对乙型肝炎病毒转染细胞基因表达的影响[J].生物化学与生物物理学报,2003,35(12):1053-1060.
[17] Wieland SF, Vega RG, Müller R, et al. Searching for interferon-induced genes that inhibit hepatitis B virus replication in transgenic mouse hepatocytes [J]. J Virol,2003, 77(2):1227-1236.
[18] Chen L, Borozan I, Feld J, et al. Hepatic gene expression discriminates respond- ers and nonresponders in treatment of chronic hepatitis C viral infection [J].Gastroenterology, 2005,128(5):1437-1444.
[19] Asselah T,Bieche I,Narguet S,et al.Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C [J].Gut,2008,57(4):516-524
[20] Honda M, Sakai A, Yamashita T,et al. Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C [J]. Gastroenterology,2010,139(2):499-509
[21] Feld JJ, Nanda S, Huang Y, et al.Hepatic gene expression during treatment with peginterferon and ribavirin: identifying molecular pathways for treatment response [J]. Hepatology, 2007, 46(5): 1548-1563.
[22] Randall G,Chen L, Panis M, et al.Silencing of USP18 Potentiates the Antiviral Activity of Interferon Against Hepatitis C Virus Infection [J]. Gastroenterology, 2006, 131(5):1584-1591.
[23]奚敏,臧国庆,冯明亮,等.慢性乙型肝炎干扰素疗效与人类白细胞抗原-等位基因的关系[J].中华传染病杂志,2004,22(4):242-245.
[24] Han YN, Yang JL, Zheng SG, et al. Relationship of human leukocyte antigen class II genes with the susceptibility to hepatitis B virus infection and the response to interferon in HBV-infected patients [J].World J Gastroenterol, 2005,11 (36): 5721-5724
[25]焦健,王江滨.丙型肝炎病毒基因型及患者人类白细胞抗原对其抗病素疗效的影响[J].中华肝脏病杂志,2003,11(10):620-622.
[26] Tan.H., J. Derrick, J. Hong, et al. Global transcriptional profiling combination of type I and type II demonstrates the interferon enhances antiviral and immune responses at clinically relevant doses [J]. J Interferon Cytokine Res,2005,25(10):632–649.
[27] Knapp S, Yee LJ, Frodsham AJ,et al. Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR [J].Genes Immun,2003 ,4(6):411-9.
[28] King JK,Yeh SH,Lin MW,et al.Genetic polymorphisms in interferon pathway and response to interferon treatment in hepatitis B patients:A pilot study [J]. Hepatology, 2002,36(6):1416-1424.
[29] Hijikata M, Mishiro S, Miyamoto C, Furuichi Y, Hashimoto M, Ohta Y. Genetic polymorphism of the MxA gene promoter and interferon responsiveness of hepatitis C patients: revisited by analyzing two SNP sites (-123 and -88) in vivo and in vitro [J]. Intervirology, 2001,44(6):379-382.
[30] Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance [J]. Nature,2009,461(7262): 399-401.
[31] Rauch A, Kutalik Z, Descombes P, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure :a genome-wide association study [J]. Gastroenterology,2010,138(4): 1338–1345.
[32] Mangia A, Thompson AJ, Santoro R et al. An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2 or 3 patients who do not achieve a rapid virologic response [J]. Gastroenterology,2010,139:821-827.
[33] Moons K, Altman D, Vergouwe Y, et al. Prognosis and prognostic research: application and impact of prognostic models in clinical practice [J]. BMJ,2009,338:b606.
[34] Aparicio E, Parera M, Franco S,et al. IL28B SNP rs8099917 Is Strongly Associated with Pegylated Interferon-αand Ribavirin Therapy Treatment Failure in HCV/HIV-1 Coinfected Patients [J]. PLoS One, 2010, 5(10):e13771.
[35] Urban TJ, Thompson AJ, Bradrick SS,et al. IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C [J]. Hepatology, 2010, 52(6):1888-96. doi: 10.1002/hep.23912.Epub 2010 Oct 7
[36] Honda M, Sakai A, Yamashita T,et al.Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C [J]. Gastroenterology,2010,139(2):499-509
[37]黄雁翔,马丽娜,陈新月,等.粘病毒抵抗蛋白A和真核细胞起始因子2α调节区2基因多态性与慢性乙型肝炎干扰素治疗效果的相关性[J].中华肝脏病杂志.2007,15(3):187-191
[38] Tsukada H, Ochi H, Maekawa T, et al. A polymorphism in MAPKAPK3 affects response to interferon therapy for chronic hepatitis C [J]. Gastroenterology, 2009, 136(5):1796-805.
[39] Chambers TJ, Fan X, Droll DA, et al. Quasispecies Heterogeneity within the E1/E2 Region as a Pretreatment Variable during Pegylated Interferon Therapy of Chronic Hepatitis C Virus Infection [J].J Virol,2005,79(5):3071–3083.