Format

Send to

Choose Destination
Gastroenterology. 2017 Aug;153(2):566-578.e5. doi: 10.1053/j.gastro.2017.04.021. Epub 2017 Apr 26.

Tumor Necrosis Factor Inhibits Spread of Hepatitis C Virus Among Liver Cells, Independent From Interferons.

Author information

1
Kennedy Institute of Rheumatology, The University of Oxford, Oxford, United Kingdom; Peter Medawar Building for Pathogen Research, The University of Oxford, Oxford, United Kingdom.
2
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York.
3
Kennedy Institute of Rheumatology, The University of Oxford, Oxford, United Kingdom.
4
Kennedy Institute of Rheumatology, The University of Oxford, Oxford, United Kingdom; Peter Medawar Building for Pathogen Research, The University of Oxford, Oxford, United Kingdom; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York. Electronic address: lynn.dustin@kennedy.ox.ac.uk.

Abstract

BACKGROUND & AIMS:

Tumor necrosis factor (TNF) is an inflammatory cytokine expressed by human fetal liver cells (HFLCs) after infection with cell culture-derived hepatitis C virus (HCV). TNF has been reported to increase entry of HCV pseudoparticles into hepatoma cells and inhibit signaling by interferon alpha (IFNα), but have no effect on HCV-RNA replication. We investigated the effects of TNF on HCV infection of and spread among Huh-7 hepatoma cells and primary HFLCs.

METHODS:

Human hepatoma (Huh-7 and Huh-7.5) and primary HFLCs were incubated with TNF and/or recombinant IFNA2A, IFNB, IFNL1, and IFNL2 before or during HCV infection. We used 2 fully infectious HCV chimeric viruses of genotype 2A in these studies: J6/JFH (clone 2) and Jc1(p7-nsGluc2A) (Jc1G), which encodes a secreted luciferase reporter. We measured HCV replication, entry, spread, production, and release in hepatoma cells and HFLCs.

RESULTS:

TNF inhibited completion of the HCV infectious cycle in hepatoma cells and HFLCs in a dose-dependent and time-dependent manner. This inhibition required TNF binding to its receptor. Inhibition was independent of IFNα, IFNβ, IFNL1, IFNL2, or Janus kinase signaling via signal transducer and activator of transcription. TNF reduced production of infectious viral particles by Huh-7 and HFLC, and thereby reduced the number of infected cells and focus size. TNF had little effect on HCV replicons and increased entry of HCV pseudoparticles. When cells were incubated with TNF before infection, the subsequent antiviral effects of IFNs were increased.

CONCLUSIONS:

In a cell culture system, we found TNF to have antiviral effects independently of, as well as in combination with, IFNs. TNF inhibits HCV infection despite increased HCV envelope glycoprotein-mediated infection of liver cells. These findings contradict those from other studies, which have reported that TNF blocks signal transduction in response to IFNs. The destructive inflammatory effects of TNF must be considered along with its antiviral effects.

KEYWORDS:

Immune Regulation; Innate Immunity; Liver Disease; Viral Infection

PMID:
28456632
PMCID:
PMC5627365
DOI:
10.1053/j.gastro.2017.04.021
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center