title: Interferon-induced proteins with tetratricopeptide repeats 1 and 2 are cellular factors that limit hepatitis B virus replication.
abstract: Interferon (IFN)-α is able to stimulate many cellular genes and inhibit the replication of various viruses. However, it is unknown whether some IFN-stimulated genes (ISGs) specifically inhibit hepatitis B virus (HBV) replication. Therefore, we attempted to identify ISGs with antiviral activities against HBV. Knockdown of IFN-induced proteins with tetratricopeptide repeats 1 and 2 (IFIT1 and IFIT2) in HepG2.2.15 led to markedly increased HBV replication. Consistently, this effect was verified by transient transfection with a replication-competent HBV clone in HepG2 and Huh7. However, IFN-α stimulation could override the knockdown by siRNAs and enhance the expression of IFIT1 and IFIT2, leading to reduced HBV replication. Silencing of IFIT1 or IFIT2 decreased the expression of the corresponding genes while other ISGs like MxA were not affected. Northern blot analysis showed that IFIT1 and IFIT2 knockdown slightly increased the levels of HBV 3.5, 2.4 and 2.1 kb transcripts, while IFIT1 and IFIT2 overexpression did not change their levels. Consistently, the reporter assays with HBV promoters demonstrated that IFIT1 and IFIT2 differentially but only modestly regulated HBV promoter activity. Thus, IFIT1 and IFIT2 contribute significantly to the regulation of HBV replication, likely at both transcriptional and posttranscriptional steps.
authors.affiliation: Institute of Virology, University Hospital of Essen, Essen, Germany.
authors.forename: Rongjuan
authors.initials: R
authors.lastname: Pei
authors.forename: Bo
authors.initials: B
authors.lastname: Qin
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Zhang
authors.forename: Wandi
authors.initials: W
authors.lastname: Zhu
authors.forename: Thekla
authors.initials: T
authors.lastname: Kemper
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Ma
authors.forename: Martin
authors.initials: M
authors.lastname: Trippler
authors.forename: Joerg
authors.initials: J
authors.lastname: Schlaak
authors.forename: Xinwen
authors.initials: X
authors.lastname: Chen
authors.forename: Mengji
authors.initials: M
authors.lastname: Lu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology / Q000821:virology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000276:immunology; D056945:Hep G2 Cells; D006514:Hepatitis B Surface Antigens / Q000276:immunology / Q000378:metabolism; D006513:Hepatitis B e Antigens / Q000276:immunology / Q000378:metabolism; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D011506:Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D034622:RNA Interference / Q000276:immunology; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014779:Virus Replication / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; C484290:IFIT1 protein, human; C484289:IFIT2 protein, human; D016898:Interferon-alpha; D011506:Proteins; D016601:RNA-Binding Proteins