Original ResearchBasic and Translational—LiverInterferon-γ–Stimulated Genes, but Not USP18, Are Expressed in Livers of Patients With Acute Hepatitis C
Section snippets
Patients
All patients were recruited in the Hepatology Outpatient Clinic of the University Hospital Basel (Basel, Switzerland). From October 2007 to December 2010, 6 patients with AHC (between 0 and 6 months after the HCV transmission) gave written informed consent to participate in this study and donated a liver biopsy specimen for research purposes. The study was approved by the Ethics Committee of Basel.
Liver biopsy specimens from 16 patients with CHC and 4 normal liver tissue samples were used for
Host–Virus Interactions During Acute Hepatitis C Induce a Distinct Pattern of Gene Expression in the Liver
Six patients with HCV monoinfection underwent a liver biopsy 2–5 months after HCV transmission (ie, during the acute phase of HCV infection) (Table 1). Gene expression in these liver biopsy specimens was analyzed with Affymetrix U133 Plus 2.0 arrays and compared with 4 samples from patients without liver disease (controls) and 16 samples from patients with CHC recruited in a previous study.7 We found between 203 and 492 genes (average, 312) up-regulated and 239 to 374 genes (average, 294)
Discussion
The study of the acute phase of HCV infection in human beings is hampered by the fact that most cases are asymptomatic. Spontaneous clearance occurs in about 20%–30% of patients.25 Studies of subjects after needlestick injuries revealed a very rapid increase of HCV viral load to maximal levels within the first 2–4 weeks.20 Viral replication then is slowed down, most likely by an innate immune response involving the induction of ISGs in the liver.14, 19 HCV-specific T cells are detectable 5–9
Acknowledgments
The authors thank the patients who participated in this study. The authors are grateful to Tanja Dietsche for excellent technical assistance with immunohistochemistry, Philippe Demougin (Life Sciences Training Facility, Pharmazentrum, Basel, Switzerland) for providing technical help with the processing of microarrays, and Sarah Durand and Cathy Royer (Inserm U748) for isolation and culture of primary human hepatocytes.
References (33)
- et al.
Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection
Gastroenterology
(2005) - et al.
Interferon-induced gene expression is a stronger predictor of treatment response than IL28B genotype in patients with hepatitis C
Gastroenterology
(2011) - et al.
Acute hepatitis C: current status and remaining challenges
J Hepatol
(2008) - et al.
Hepatitis C virus blocks interferon effector function by inducing protein kinase R phosphorylation
Cell Host Microbe
(2009) - et al.
Targeted impairment of innate antiviral responses in the liver of chronic hepatitis C patients
J Hepatol
(2012) The global burden of hepatitis C
Liver Int
(2009)EASL Clinical Practice Guidelines: management of hepatitis C virus infection
J Hepatol
(2011)- et al.
A new standard of care for the treatment of chronic HCV infection
Nat Rev Gastroenterol Hepatol
(2011) - et al.
Boceprevir for untreated chronic HCV genotype 1 infection
N Engl J Med
(2011) - et al.
Boceprevir for previously treated chronic HCV genotype 1 infection
N Engl J Med
(2011)
Interferon signaling and treatment outcome in chronic hepatitis C
Proc Natl Acad Sci U S A
Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C
Gut
Alpha interferon induces long-lasting refractoriness of JAK-STAT signaling in the mouse liver through induction of USP18/UBP43
Mol Cell Biol
Treatment of acute hepatitis C with interferon alfa-2b
N Engl J Med
Early monotherapy with pegylated interferon alpha-2b for acute hepatitis C infection: the HEP-NET acute-HCV-II study
Hepatology
DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection
J Virol
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2017, Trends in MicrobiologyVirology and Pathogenesis of Hepatitis C
2017, Zakim and Boyer's Hepatology: A Textbook of Liver DiseaseHCV infection, IFN response and the coding and non-coding host cell genome
2016, Virus ResearchHost – hepatitis C viral interactions: The role of genetics
2016, Journal of HepatologyCitation Excerpt :Third, IFNα cannot be the driver of ISG expression because IFNα signaling is refractory in these patients [29,30]. Refractoriness or non-response to IFNα is most likely caused by USP18, a classical ISG itself and a strong inhibitor of IFNα receptor signaling that is highly expressed in the liver of patients with CHC and high ISG expression [19,31,32]. During the 25 years of (Peg)IFNα based treatments for CHC, the clinical consequence of this refractoriness was non-response to treatment (reviewed in [33]).
M.T.D. and Z.M. contributed equally to this work.
Conflicts of interest The authors disclose no conflicts.
Funding Supported by Swiss National Science Foundation grants 320030_130243 (M.H.H.) and 323500-123714 (M.T.D.).