Original ResearchBasic and Translational—LiverHCV Infection Induces a Unique Hepatic Innate Immune Response Associated With Robust Production of Type III Interferons
Section snippets
Cells and Virus
Detailed information on the cells used in this study is included in Supplementary Materials and Methods. The HCV JFH114 strain was used in cell culture experiments at a multiplicity of infection (MOI) of 0.5 unless otherwise indicated. The HCV JFH1-Luciferase virus was provided by C. Rice (Rockefeller University, New York, NY).
Reagents
HCV PAMP RNA was generated from a plasmid containing the 3′ and 5′ untranslated regions of HCV that was previously reported.15 Anti-HCV E2 antibody (AP33) was described
Expression of IL-28 in Chimpanzee and Human Models of HCV Infection
HCV infection in both humans and chimpanzees induces high levels of ISGs in the infected liver, but the direct stimulus for ISG induction remains unclear.6, 7 To explore the mechanism of this ISG induction, we studied liver biopsy specimens from chimpanzees obtained before and after HCV infection. Gene expression analysis using qPCR showed a robust up-regulation of IL-28 but minimal type I or II IFN in the liver of these animals early following HCV infection (Figure 1A). The induction of IL-28
Discussion
In patients and chimpanzees infected with HCV, a robust antiviral response can be detected in the liver. A published study had previously investigated and characterized HCVcc infection of PHHs.26 However, to our knowledge, this study represents the first extensive characterization of the intrinsic innate immune response in adult PHHs following in vitro infection by HCVcc. We reproducibly show the production of IL-28 protein at the nanogram level in response to HCV nucleic acid PAMP and
Acknowledgments
E.T. and V.D.G. contributed equally to this work.
References (27)
TLRs and innate immunity
Blood
(2009)- et al.
Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics
Gastroenterology
(2006) - et al.
Viral infections activate types I and III interferon genes through a common mechanism
J Biol Chem
(2007) - et al.
The roles of TLRs, RLRs and NLRs in pathogen recognition
Int Immunol
(2009) - et al.
Regulation of adaptive immunity by the innate immune system
Science
(2010) - et al.
Innate immunity to virus infection
Immunol Rev
(2009) - et al.
Type I interferon production induced by RIG-I-like receptors
J Interferon Cytokine Res
(2010) - et al.
Intrahepatic gene expression during chronic hepatitis C virus infection in chimpanzees
J Virol
(2004) - et al.
Interferon signaling and treatment outcome in chronic hepatitis C
Proc Natl Acad Sci U S A
(2008) - et al.
Genomic analysis of the host response to hepatitis C virus infection
Proc Natl Acad Sci U S A
(2002)
Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA
Nature
IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex
Nat Immunol
Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C
Nat Genet
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PHH cultures were provided by the National Institutes of Health–funded Liver Tissue Procurement and Cell Distribution System (N01-DK-7-0004/HHSN26700700004C) (principal investigator: Stephen Strom, University of Pittsburgh).
The authors thank Stephen Feinstone for providing the liver biopsy samples from chimpanzee CH6412.
Conflicts of interest The authors disclose no conflicts.
Funding Supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. E.T. was supported by funding from the National Institutes of Health Loan Repayment Program. V.D.G. was supported by the Swedish Research Council and the Wenner-Gren Foundation. PHH cultures were provided by the National Institutes of Health–funded Liver Tissue Procurement and Cell Distribution System (N01-DK-7-0004/HHSN26700700004C) (principal investigator: Stephen Strom, University of Pittsburgh).