The hepatitis C virus non-structural NS5A protein impairs both the innate and adaptive hepatic immune response in vivo.
The role of hepatitis C virus (HCV) protein non-structural (NS) 5A in HCV-associated pathogenesis is still enigmatic. To investigate the in vivo role of NS5A for viral persistence and virus-associated pathogenesis a transgenic (Tg) mouse model was established. Mice with liver-targeted NS5A transgene expression were generated using the albumin promoter. Alterations in the hepatic immune response were determined by Western blot, infection by lymphocytic choriomeningitis virus (LCMV), and using transient NS3/4A Tg mice generated by hydrodynamic injection. Cytotoxic T lymphocyte (CTL) activity was investigated by the Cr-release assay. The stable NS5A Tg mice did not reveal signs of spontaneous liver disease. The intrahepatic immunity was disrupted in the NS5A Tg mice as determined by clearance of LCMV infection or transiently NS3/4A Tg hepatocytes in vivo. This impaired immunity was explained by a reduced induction of interferon beta, 2',5'-OAS, and PKR after LCMV infection and an impairment of the CTL-mediated elimination of NS3-expressing hepatocytes. In conclusion, these data indicate that in the present transgenic mouse model, NS5A does not cause spontaneous liver disease. However, we discovered that NS5A could impair both the innate and the adaptive immune response to promote chronic HCV infection.
Kriegs
Malte
M
Department of Internal Medicine II, University of Freiburg, D-79106 Freiburg, Germany; Heinrich-Pette-Institute for Experimental Virology and Immunology, D-20251 Hamburg, Germany; Robert-Koch-Institute, D-13353 Berlin, Germany; Division of Clinical Microbiology F68, Karolinska University Hospital Huddinge, Karolinska Institutet, S-141 86 Stockholm, Sweden.
Bürckstümmer
Tilmann
T
Robert-Koch-Institute, D-13353 Berlin, Germany.
Himmelsbach
Kyoshi
K
Department of Internal Medicine II, University of Freiburg, D-79106 Freiburg, Germany; Institute of Infection Medicine, University of Kiel, D-24105 Kiel, Germany.
Bruns
Michael
M
Heinrich-Pette-Institute for Experimental Virology and Immunology, D-20251 Hamburg, Germany.
Frelin
Lars
L
Division of Clinical Microbiology F68, Karolinska University Hospital Huddinge, Karolinska Institutet, S-141 86 Stockholm, Sweden.
Ahlén
Gustaf
G
Division of Clinical Microbiology F68, Karolinska University Hospital Huddinge, Karolinska Institutet, S-141 86 Stockholm, Sweden.
Sällberg
Matti
M
Division of Clinical Microbiology F68, Karolinska University Hospital Huddinge, Karolinska Institutet, S-141 86 Stockholm, Sweden.
Hildt
Eberhard
E
Department of Internal Medicine II, University of Freiburg, D-79106 Freiburg, Germany; Institute of Infection Medicine, University of Kiel, D-24105 Kiel, Germany. Electronic address: hildt@infmed.uni-kiel.de.
D000818:Animals; D020869:Gene Expression Profiling; D016174:Hepacivirus / Q000378:metabolism*; D007113:Immunity, Innate / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology*; D012324:RNA-Dependent RNA Polymerase
D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
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