Expression of hepatitis C virus proteins inhibits interferon α signaling in the liver of transgenic mice

Alex Blindenbacher, Francois H T Duong, Lukas Hunziker, Simone T D Stutvoet, Xueya Wang, Luigi Terracciano, Darius Moradpour, Hubert E. Blum, Tonino Alonzi, Marco Tripodi, Nicola La Monica, Markus H. Heim

Research output: Contribution to journalArticle

Abstract

Background & Aims: Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. The majority of patients treated with interferon alpha do not have a sustained response with clearance of the virus. The molecular mechanisms underlying interferon resistance are poorly understood. Interferon-induced activation of the Jak-STAT (signal transducer and activator of transcription) signal transduction pathway is essential for the induction of an antiviral state. Interference of viral proteins with the Jak-STAT pathway could be responsible for interferon resistance in patients with chronic HCV. Methods: We have analyzed interferon-induced signal transduction through the Jak-STAT pathway in transgenic mice that express HCV proteins in their liver cells. STAT activation was investigated with Western blots, immunofluorescence, and electrophoretic mobility shift assays. Virus challenge experiments with lymphocytic choriomeningitis virus were used to demonstrate the functional importance of Jak-STAT inhibition. Results: STAT signaling was found to be strongly inhibited in liver cells of HCV transgenic mice. The inhibition occurred in the nucleus and blocked binding of STAT transcription factors to the promoters of interferon-stimulated genes. Tyrosine phosphorylation of STAT proteins by Janus kinases at the interferon receptor was not inhibited. This lack in interferon response resulted in an enhanced susceptibility of the transgenic mice to infection with a hepatotropic strain of lymphocytic choriomeningitis virus. Conclusions: Interferon-induced intracellular signaling is impaired in HCV transgenic mice. Interference of HCV proteins with interferon-induced intracellular signaling could be an important mechanism of viral persistence and treatment resistance.

Original languageEnglish
Pages (from-to)1465-1475
Number of pages11
JournalGastroenterology
Volume124
Issue number5
DOIs
Publication statusPublished - May 1 2003

Fingerprint

Hepacivirus
Interferons
Transgenic Mice
Liver
Proteins
Lymphocytic choriomeningitis virus
Signal Transduction
STAT Transcription Factors
Interferon Receptors
Viruses
Janus Kinases
Electrophoretic Mobility Shift Assay
Viral Proteins
Chronic Hepatitis C
Transducers
Interferon-alpha
Liver Cirrhosis
Protein Kinases
Antiviral Agents
Fluorescent Antibody Technique

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Blindenbacher, A., Duong, F. H. T., Hunziker, L., Stutvoet, S. T. D., Wang, X., Terracciano, L., ... Heim, M. H. (2003). Expression of hepatitis C virus proteins inhibits interferon α signaling in the liver of transgenic mice. Gastroenterology, 124(5), 1465-1475. https://doi.org/10.1016/S0016-5085(03)00290-7

Expression of hepatitis C virus proteins inhibits interferon α signaling in the liver of transgenic mice. / Blindenbacher, Alex; Duong, Francois H T; Hunziker, Lukas; Stutvoet, Simone T D; Wang, Xueya; Terracciano, Luigi; Moradpour, Darius; Blum, Hubert E.; Alonzi, Tonino; Tripodi, Marco; La Monica, Nicola; Heim, Markus H.

In: Gastroenterology, Vol. 124, No. 5, 01.05.2003, p. 1465-1475.

Research output: Contribution to journalArticle

Blindenbacher, A, Duong, FHT, Hunziker, L, Stutvoet, STD, Wang, X, Terracciano, L, Moradpour, D, Blum, HE, Alonzi, T, Tripodi, M, La Monica, N & Heim, MH 2003, 'Expression of hepatitis C virus proteins inhibits interferon α signaling in the liver of transgenic mice', Gastroenterology, vol. 124, no. 5, pp. 1465-1475. https://doi.org/10.1016/S0016-5085(03)00290-7
Blindenbacher A, Duong FHT, Hunziker L, Stutvoet STD, Wang X, Terracciano L et al. Expression of hepatitis C virus proteins inhibits interferon α signaling in the liver of transgenic mice. Gastroenterology. 2003 May 1;124(5):1465-1475. https://doi.org/10.1016/S0016-5085(03)00290-7
Blindenbacher, Alex ; Duong, Francois H T ; Hunziker, Lukas ; Stutvoet, Simone T D ; Wang, Xueya ; Terracciano, Luigi ; Moradpour, Darius ; Blum, Hubert E. ; Alonzi, Tonino ; Tripodi, Marco ; La Monica, Nicola ; Heim, Markus H. / Expression of hepatitis C virus proteins inhibits interferon α signaling in the liver of transgenic mice. In: Gastroenterology. 2003 ; Vol. 124, No. 5. pp. 1465-1475.
@article{1efe51efb9de4f168602480119c0aa3b,
title = "Expression of hepatitis C virus proteins inhibits interferon α signaling in the liver of transgenic mice",
abstract = "Background & Aims: Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. The majority of patients treated with interferon alpha do not have a sustained response with clearance of the virus. The molecular mechanisms underlying interferon resistance are poorly understood. Interferon-induced activation of the Jak-STAT (signal transducer and activator of transcription) signal transduction pathway is essential for the induction of an antiviral state. Interference of viral proteins with the Jak-STAT pathway could be responsible for interferon resistance in patients with chronic HCV. Methods: We have analyzed interferon-induced signal transduction through the Jak-STAT pathway in transgenic mice that express HCV proteins in their liver cells. STAT activation was investigated with Western blots, immunofluorescence, and electrophoretic mobility shift assays. Virus challenge experiments with lymphocytic choriomeningitis virus were used to demonstrate the functional importance of Jak-STAT inhibition. Results: STAT signaling was found to be strongly inhibited in liver cells of HCV transgenic mice. The inhibition occurred in the nucleus and blocked binding of STAT transcription factors to the promoters of interferon-stimulated genes. Tyrosine phosphorylation of STAT proteins by Janus kinases at the interferon receptor was not inhibited. This lack in interferon response resulted in an enhanced susceptibility of the transgenic mice to infection with a hepatotropic strain of lymphocytic choriomeningitis virus. Conclusions: Interferon-induced intracellular signaling is impaired in HCV transgenic mice. Interference of HCV proteins with interferon-induced intracellular signaling could be an important mechanism of viral persistence and treatment resistance.",
author = "Alex Blindenbacher and Duong, {Francois H T} and Lukas Hunziker and Stutvoet, {Simone T D} and Xueya Wang and Luigi Terracciano and Darius Moradpour and Blum, {Hubert E.} and Tonino Alonzi and Marco Tripodi and {La Monica}, Nicola and Heim, {Markus H.}",
year = "2003",
month = "5",
day = "1",
doi = "10.1016/S0016-5085(03)00290-7",
language = "English",
volume = "124",
pages = "1465--1475",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "5",

}

TY - JOUR

T1 - Expression of hepatitis C virus proteins inhibits interferon α signaling in the liver of transgenic mice

AU - Blindenbacher, Alex

AU - Duong, Francois H T

AU - Hunziker, Lukas

AU - Stutvoet, Simone T D

AU - Wang, Xueya

AU - Terracciano, Luigi

AU - Moradpour, Darius

AU - Blum, Hubert E.

AU - Alonzi, Tonino

AU - Tripodi, Marco

AU - La Monica, Nicola

AU - Heim, Markus H.

PY - 2003/5/1

Y1 - 2003/5/1

N2 - Background & Aims: Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. The majority of patients treated with interferon alpha do not have a sustained response with clearance of the virus. The molecular mechanisms underlying interferon resistance are poorly understood. Interferon-induced activation of the Jak-STAT (signal transducer and activator of transcription) signal transduction pathway is essential for the induction of an antiviral state. Interference of viral proteins with the Jak-STAT pathway could be responsible for interferon resistance in patients with chronic HCV. Methods: We have analyzed interferon-induced signal transduction through the Jak-STAT pathway in transgenic mice that express HCV proteins in their liver cells. STAT activation was investigated with Western blots, immunofluorescence, and electrophoretic mobility shift assays. Virus challenge experiments with lymphocytic choriomeningitis virus were used to demonstrate the functional importance of Jak-STAT inhibition. Results: STAT signaling was found to be strongly inhibited in liver cells of HCV transgenic mice. The inhibition occurred in the nucleus and blocked binding of STAT transcription factors to the promoters of interferon-stimulated genes. Tyrosine phosphorylation of STAT proteins by Janus kinases at the interferon receptor was not inhibited. This lack in interferon response resulted in an enhanced susceptibility of the transgenic mice to infection with a hepatotropic strain of lymphocytic choriomeningitis virus. Conclusions: Interferon-induced intracellular signaling is impaired in HCV transgenic mice. Interference of HCV proteins with interferon-induced intracellular signaling could be an important mechanism of viral persistence and treatment resistance.

AB - Background & Aims: Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. The majority of patients treated with interferon alpha do not have a sustained response with clearance of the virus. The molecular mechanisms underlying interferon resistance are poorly understood. Interferon-induced activation of the Jak-STAT (signal transducer and activator of transcription) signal transduction pathway is essential for the induction of an antiviral state. Interference of viral proteins with the Jak-STAT pathway could be responsible for interferon resistance in patients with chronic HCV. Methods: We have analyzed interferon-induced signal transduction through the Jak-STAT pathway in transgenic mice that express HCV proteins in their liver cells. STAT activation was investigated with Western blots, immunofluorescence, and electrophoretic mobility shift assays. Virus challenge experiments with lymphocytic choriomeningitis virus were used to demonstrate the functional importance of Jak-STAT inhibition. Results: STAT signaling was found to be strongly inhibited in liver cells of HCV transgenic mice. The inhibition occurred in the nucleus and blocked binding of STAT transcription factors to the promoters of interferon-stimulated genes. Tyrosine phosphorylation of STAT proteins by Janus kinases at the interferon receptor was not inhibited. This lack in interferon response resulted in an enhanced susceptibility of the transgenic mice to infection with a hepatotropic strain of lymphocytic choriomeningitis virus. Conclusions: Interferon-induced intracellular signaling is impaired in HCV transgenic mice. Interference of HCV proteins with interferon-induced intracellular signaling could be an important mechanism of viral persistence and treatment resistance.

UR - http://www.scopus.com/inward/record.url?scp=0037621934&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037621934&partnerID=8YFLogxK

U2 - 10.1016/S0016-5085(03)00290-7

DO - 10.1016/S0016-5085(03)00290-7

M3 - Article

C2 - 12730885

AN - SCOPUS:0037621934

VL - 124

SP - 1465

EP - 1475

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 5

ER -