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Antiviral Res. 2016 Jun;130:36-45. doi: 10.1016/j.antiviral.2016.03.008. Epub 2016 Mar 10.

Antiviral activity of various interferons and pro-inflammatory cytokines in non-transformed cultured hepatocytes infected with hepatitis B virus.

Author information

1
INSERM U1052, Cancer Research Centre of Lyon (CRCL), 69424 Lyon Cedex 03, France; University of Lyon, Université Claude Bernard (UCBL), UMR_S1052, 69008 Lyon, France; LabEx DEVweCAN, 69008 Lyon, France.
2
INSERM U1032, 69424 Lyon Cedex 03, France.
3
INSERM U1052, Cancer Research Centre of Lyon (CRCL), 69424 Lyon Cedex 03, France; University of Lyon, Université Claude Bernard (UCBL), UMR_S1052, 69008 Lyon, France; LabEx DEVweCAN, 69008 Lyon, France; Hospices Civils de Lyon (HCL), Liver Departement of Croix-Rousse Hospital, 69002 Lyon, France; Institut Universitaire de France (IUF), 75005 Paris, France. Electronic address: fabien.zoulim@inserm.fr.
4
INSERM U1052, Cancer Research Centre of Lyon (CRCL), 69424 Lyon Cedex 03, France; University of Lyon, Université Claude Bernard (UCBL), UMR_S1052, 69008 Lyon, France; LabEx DEVweCAN, 69008 Lyon, France. Electronic address: david.durantel@inserm.fr.

Abstract

In HBV-infected patients, therapies with nucleoside analogues or IFNα remain ineffective in eradicating the infection. Our aim was to re-analyze the anti-HBV activity of a large panel of IFNs and cytokines in vitro using non-transformed cultured hepatocytes infected with HBV, to identify new immune-therapeutic options. HepaRG cells and primary human hepatocytes were infected with HBV and, when infection was established, treated with various concentrations of different IFNs or inflammatory cytokines. Viral parameters were evaluated by quantifying HBV nucleic acids by qPCR and Southern Blot, and secreted HBV antigens were evaluated using ELISA. The cytokines tested were type-I IFNs, IFNγ, type-III IFNs, TNFα, IL-6, IL-1β, IL-18 as well as nucleos(t)ide analogues tenofovir and ribavirin. Cytokines and drugs, with the exception of IL-18 and ribavirin, exhibited a suppressive effect on HBV replication at least as strong as, but often stronger than, IFNα. The cytokine presenting the highest effect on HBV DNA was IL-1β, which exerted its inhibition within picomolar range. Importantly, we noticed differential effects on other parameters (HBV RNA, HBeAg, HBsAg) between both IFNs and inflammatory cytokines, thus suggesting different mechanisms of action. The combination of IL-1β and already used therapies, i.e. IFNα or tenofovir, demonstrated a stronger or similar anti-HBV activity. IL-1β was found to have a very potent antiviral effect against HBV in vitro. HBV was previously shown to promptly inhibit IL-1β production in Kupffer cells. Strategies aiming at unlocking this inhibition and restoring local production of IL-1β may help to further inhibit HBV replication in vivo.

KEYWORDS:

Antiviral effect; Hepatitis B virus; Immune-modulators; Innate immunity; Interferons; Pro-inflammatory cytokines

PMID:
26971407
DOI:
10.1016/j.antiviral.2016.03.008
[Indexed for MEDLINE]

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