Targeted impairment of innate antiviral responses in the liver of chronic hepatitis C patients.

Abstract:

BACKGROUND & AIMS:Innate sensing of viral infection activates a global defense response including type I interferon (IFN) and IFN-stimulated genes (ISGs) expression. We previously reported that HCV NS3/4A protease, an essential protein in viral polyprotein processing, can abrogate antiviral signaling pathways and effectors' response when ectopically expressed in human hepatocytes by cleaving antiviral adaptor CARDIF. However, whether HCV mediates evasion of innate immunity in patients with chronic infection remains unclear. METHODS:In this study, paired liver biopsies and corresponding purified hepatocytes of chronic hepatitis C patients and controls were subjected to transcriptional analysis of selected innate immune genes and to CARDIF protein detection. RESULTS:We report that an antiviral response is largely supported by infected hepatocytes as demonstrated by upregulation of the representative antiviral genes ISG15, ISG56, and OASL as well as chemokines genes CXCL9, CXCL10, and CXCL11 measured in both HCV-derived liver biopsies and hepatocytes; that the mRNA levels of these indicator ISGs correlate inversely with HCV RNA level; and more importantly that expression of the early responsive IRF3-dependent genes type I IFNβ, type III IL28A/IL29, and chemokine CCL5 are severely compromised and associated to a global decrease of CARDIF adaptor in infected hepatocytes. CONCLUSIONS:Altogether the data argue for a strong viral strategy that counteracts the host's early antiviral response of hepatocytes from chronic patients without impairing ISGs induced via classical IFN pathway.

journal_name

J Hepatol

journal_title

Journal of hepatology

authors

Jouan L,Chatel-Chaix L,Melançon P,Rodrigue-Gervais IG,Raymond VA,Selliah S,Bilodeau M,Grandvaux N,Lamarre D

doi

10.1016/j.jhep.2011.07.017

subject

Has Abstract

pub_date

2012-01-01 00:00:00

pages

70-7

issue

1

eissn

0168-8278

issn

1600-0641

pii

S0168-8278(11)00611-8

journal_volume

56

pub_type

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