Journal article
IFNL3 genotype is associated with differential induction of IFNL3 in primary human hepatocytes
Antiviral therapy, Vol.20(8), pp.805-814
01/01/2015
DOI: 10.3851/IMP2974
PMCID: PMC4821403
PMID: 26109548
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.
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.
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).
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.
Details
- Title: Subtitle
- IFNL3 genotype is associated with differential induction of IFNL3 in primary human hepatocytes
- Creators
- Fuat Kurbanov - Johns Hopkins MedicineYonghak Kim - Johns Hopkins UniversityRachel Latanich - Johns Hopkins UniversityPooja Chaudhari - Johns Hopkins UniversityRamy El-Diwany - Johns Hopkins Sch Med, Dept Med, Div Infect Dis, Baltimore, MD USAMatt Knabel - Johns Hopkins UniversityAbraham J. Kandathil - Johns Hopkins UniversityAndrew Cameron - Johns Hopkins UniversityAndrea Cox - Johns Hopkins UniversityYoon-Young Jang - Johns Hopkins MedicineDavid L. Thomas - Johns Hopkins MedicineAshwin Balagopal - Johns Hopkins Medicine
- Resource Type
- Journal article
- Publication Details
- Antiviral therapy, Vol.20(8), pp.805-814
- DOI
- 10.3851/IMP2974
- PMID
- 26109548
- PMCID
- PMC4821403
- NLM abbreviation
- Antivir Ther
- ISSN
- 1359-6535
- eISSN
- 2040-2058
- Publisher
- Int Medical Press Ltd
- Number of pages
- 10
- Grant note
- 2010-MSCRFII-0101-00 / MSCRF grants R21AA020020 / NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) R01DA013324 / NATIONAL INSTITUTE ON DRUG ABUSE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Drug Abuse (NIDA); European Commission P30AI094189 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
- Language
- English
- Date published
- 01/01/2015
- Academic Unit
- Surgery
- Record Identifier
- 9984966749702771
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