The hepatitis C virus and immune evasion: non-structural 3/4A transgenic mice are resistant to lethal tumour necrosis factor alpha mediated liver disease.
BACKGROUND
The hepatitis C virus (HCV) establishes chronic infection by incompletely understood mechanisms. The non-structural (NS) 3/4A protease/helicase has been proposed as a key complex in modulating the infected hepatocyte, although nothing is known about the effects this complex exerts in vivo.


OBJECTIVE
To generate mice with stable and transient hepatocyte expression of the HCV NS3/4A proteins to study its effects in vivo.


METHODS
NS3/4A expression was determined by western blot and immunohistochemistry. Two independent pathologists determined the liver histology. Hepatic immunity was characterised by quantifying intrahepatic immune cell subsets. Liver damage was induced using carbon tetrachloride (CCl(4)), lipopolysaccaride (LPS), tumour necrosis factor alpha (TNFalpha), and anti-Fas antibody.


RESULTS
Expression of NS3/4A was restricted to the cytoplasm of hepatocytes, and did not cause liver cancer or any spontaneous liver pathology. However, the presence of NS3/4A modulated the intrahepatic immunity, as follows: first, the CD4+ T cell and type I/II dendritic cell subsets were reduced in transgenic livers; second, NS3/4A protected hepatocytes from liver damage mediated in vivo by CCl(4), LPS, TNFalpha, but not FAS; and third, both stable and transiently NS3/4A transgenic mice were resistant to lethal doses of liver targeted TNFalpha, and the resistance could be reverted by treatment with a p38 mitogen activated protein kinase inhibitor (MAPK).


CONCLUSIONS
Hepatic expression of NS3/4A does not induce spontaneous liver disease. NS3/4A does, however, alter the intrahepatic immune cell subsets and protects hepatocytes against TNFalpha induced liver damage in vivo. The TNFalpha resistance can be reverted by treatment with a p38 MAPK inhibitor. This represents a new immune evasion strategy conferred by NS3/4A.
Frelin
L
L
Karolinska Institutet, Division of Clinical Virology, F 68, Karolinska University Hospital, Huddinge, S-141 86 Stockholm, Sweden.
Brenndörfer
E D
ED
Ahlén
G
G
Weiland
M
M
Hultgren
C
C
Alheim
M
M
Glaumann
H
H
Rozell
B
B
Milich
D R
DR
Bode
J G
JG
Sällberg
M
M
D000818:Animals; D016174:Hepacivirus / Q000276:immunology*; D022781:Hepatocytes / Q000378:metabolism; D007150:Immunohistochemistry; D008107:Liver Diseases / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases