title: Interferon-λ4 is a cell-autonomous type III interferon associated with pre-treatment hepatitis C virus burden.
abstract: Genetic variants surrounding the interferon-λ3 (IFNL3) gene are strongly associated with clearance of hepatitis C virus (HCV). A variant (rs368234815 TT/ΔG) upstream of IFNL3 was recently implicated to control expression of a novel gene termed IFNL4. We conducted genetic analysis of rs368234815 in a chronic HCV patient cohort and molecular studies of IFNL4 in primary human hepatocytes (PHHs). Analysis of PHHs that are heterozygous at rs368234815 revealed that the IFNL4 transcript isoform is rare, accounting for 2% of transcripts arising from the IFNL4 locus. Nevertheless, IFNL4 over-expression inhibited replication of multiple Flaviviridae and IFNL4 anti-viral potency required the IFNL receptor. In contrast to IFNL3, IFNL4 was inefficiently secreted and appeared to act in a cell-autonomous manner. Genetic analysis revealed associations of rs368234815 with sustained virological response and pre-treatment viral load. The findings suggest that IFNL4 is an atypical IFNL whose activity may be maladaptive to clearance of HCV infection.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, NC 27710, USA; Center for Human Genome Variation, Duke University Medical Center, NC 27710, USA.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Lu
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, NC 27710, USA; Center for Human Genome Variation, Duke University Medical Center, NC 27710, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.affiliation: Center for Human Genome Variation, Duke University Medical Center, NC 27710, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Urban
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, NC 27710, USA; Center for Human Genome Variation, Duke University Medical Center, NC 27710, USA; Center for RNA Biology, Duke University Medical Center, NC 27710, USA.
authors.forename: Shelton S
authors.initials: SS
authors.lastname: Bradrick
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D015331:Cohort Studies; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology; D006801:Humans; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012254:Ribavirin / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D007378:Interleukins; D012254:Ribavirin; C579163:IFNL4 protein, human; D000095022:Interferon Lambda
keywords: Flaviviridae; Genome-wide association study; Hepatitis C virus; IL28B; Sustained virological response