title: Cellular Mechanism for Impaired Hepatitis C Virus Clearance by Interferon Associated with IFNL3 Gene Polymorphisms Relates to Intrahepatic Interferon-λ Expression.
abstract: The single nucleotide polymorphism located within the IFNL3 (also known as IL28B) promoter is one of the host factors associated with hepatitis C virus (HCV) clearance by interferon (IFN)-α therapy; however the mechanism remains unknown. We investigated how IL28B gene polymorphism influences HCV clearance with infected primary human hepatocytes, liver biopsies, and hepatoma cell lines. Our study confirms that the rs12979860-T/T genotype has a strong correlation with ss469415590-ΔG/ΔG single nucleotide polymorphism that produces IFN-λ4 protein. We found that IFN-α and IFN-λ1 antiviral activity against HCV was impaired in IL28B T/T infected hepatocytes compared with C/C genotype. Western blot analysis showed that IL28B TT genotype hepatocytes expressed higher levels of IFN-λ proteins (IL28B, IL-29), preactivated IFN-stimulated gene (ISG) expression, and impaired Stat phosphorylation when stimulated with either IFN-α or IFN-λ1. Furthermore, we showed that silencing IFN-λ1 in T/T cell line reduced basal ISG expression and improved antiviral activity. Likewise, overexpression of IFN-λ (1 to 4) in C/C cells induced basal ISG expression and prevented IFN-α antiviral activity. We showed that IFN-λ4, produced at low level only in T/T cells induced expression of IL28B and IL-29 and prevented IFN-α antiviral activity in HCV cell culture. Our results suggest that IFN-λ4 protein expression associated with the IL28B-T/T variant preactivates the Janus kinase-Stat signaling, leading to impaired HCV clearance by both IFN-α and IFN-λ.
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Pauline
authors.initials: P
authors.lastname: Ferraris
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Partha K
authors.initials: PK
authors.lastname: Chandra
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Panigrahi
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Fatma
authors.initials: F
authors.lastname: Aboulnasr
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Chava
authors.affiliation: Department of Medicine, Gastroenterology, and Hepatology, Tulane University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Ramazan
authors.initials: R
authors.lastname: Kurt
authors.affiliation: Department of Molecular Virology and Immunology, Institut Mondor de la Recherche, Creteil, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Pawlotsky
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Wilkens
authors.affiliation: Department of Vaccination and Immune Protection Viral Infections, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Pamela
authors.initials: P
authors.lastname: Osterlund
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors.forename: Rune
authors.initials: R
authors.lastname: Hartmann
authors.affiliation: Department of Medicine, Gastroenterology, and Hepatology, Tulane University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Balart
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Tong
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana; Department of Medicine, Gastroenterology, and Hepatology, Tulane University Health Sciences Center, New Orleans, Louisiana. Electronic address: sdash@tulane.edu.
authors.forename: Srikanta
authors.initials: S
authors.lastname: Dash
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism / Q000494:pharmacology; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008113:Liver Neoplasms / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579163:IFNL4 protein, human