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IFNL3 genotype is associated with differential induction of IFNL3 in primary human hepatocytes.
- Source :
-
Antiviral therapy [Antivir Ther] 2015; Vol. 20 (8), pp. 805-14. Date of Electronic Publication: 2015 Jun 25. - Publication Year :
- 2015
-
Abstract
- Background: Lambda interferons (IFNLs) have potent antiviral activity against HCV, and polymorphisms within the IFNL gene cluster near the IFNL3 gene strongly predict spontaneous- and treatment-related HCV infection outcomes. The mechanism(s) linking IFNL polymorphisms and HCV control is currently elusive.<br />Methods: IFNL induction was studied in primary human hepatocytes (PHH) from 18 human donors, peripheral blood mononuclear cells (PBMCs) from 18 human donors, multiple cell lines and induced pluripotent stem cell-derived hepatocyte-like cells (iPSC-hepatocytes) from 7 human donors. After stimulation with intracellular RNA and infectious HCV, quantitative PCR (qPCR) primers and probes were designed to distinguish and quantify closely related IFNL messenger (m)RNAs from IFNL1, IFNL2 and IFNL3.<br />Results: PHH demonstrated the most potent induction of IFNLs, although had lower pre-stimulation levels compared to PBMCs, monocytes and cell lines. PHH stimulation with cytoplasmic poly I:C induced >1,000-fold expression of IFNL1, IFNL2 and IFNL3. PHH from donors who were homozygous for the favourable IFNL3 allele (IFNL3-CC) had higher IFNL3 induction compared to PHH from IFNL3-TT donors (P=0.03). Baseline IFNL mRNA expression and induction was also tested in iPSC-hepatocytes: iPSC-hepatocytes had significantly higher baseline expression of IFNLs compared to PHH (P<0.0001), and IFNL3 induction was marginally different in iPSC-hepatocytes by IFNL genotype (P=0.07).<br />Conclusions: Hepatocytes express IFNLs when stimulated by a synthetic viral RNA that signals the cell through the cytoplasm. IFNL induction may be greater in persons with the favourable IFNL3 allele. These data provide insight into the strong linkage between IFNL3 genetics and control of HCV infection.
- Subjects :
- Adolescent
Adult
Aged
Cell Line
Child
Female
Hepacivirus
Hepatitis C genetics
Hepatitis C metabolism
Hepatitis C virology
Hepatocytes cytology
Humans
Induced Pluripotent Stem Cells cytology
Induced Pluripotent Stem Cells drug effects
Induced Pluripotent Stem Cells metabolism
Interferons
Male
Middle Aged
Polymorphism, Single Nucleotide
RNA, Messenger genetics
RNA, Messenger metabolism
Transcription, Genetic
Young Adult
Gene Expression Regulation
Genotype
Hepatocytes metabolism
Interleukins genetics
Interleukins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2040-2058
- Volume :
- 20
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Antiviral therapy
- Publication Type :
- Academic Journal
- Accession number :
- 26109548
- Full Text :
- https://doi.org/10.3851/IMP2974