Insights on the antiviral mechanisms of action of the TLR1/2 agonist Pam3CSK4 in hepatitis B virus (HBV)-infected hepatocytes

Pegylated-interferon-alpha (Peg-IFNα), an injectable innate immune protein, is still used to treat chronically HBV-infected patients, despite its poor tolerability. Peg-IFNα has the advantage over nucleos(t)ide analogues (NAs) to be administrated in finite regimen and to lead to a higher HBsAg loss...

Full description

Saved in:

Bibliographic Details
Published in:	Antiviral research Vol. 206; p. 105386
Main Authors:	Desmares, Manon, Delphin, Marion, Chardès, Brieux, Pons, Caroline, Riedinger, Juliette, Michelet, Maud, Rivoire, Michel, Verrier, Bernard, Salvetti, Anna, Lucifora, Julie, Durantel, David
Format:	Journal Article
Language:	English
Published:	Elsevier B.V 01-10-2022 Elsevier Masson
Subjects:	Antiviral activity FEN-1 Hepatitis B virus Hepatocytes Life Sciences Microbiology and Parasitology NF-κB pathway TLR2 agonist Toll-like receptor 1/2 Virology Toll-like receptor 1/2 Hepatocytes TLR2 agonist Antiviral activity NF-κB pathway FEN-1 Hepatitis B virus
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Pegylated-interferon-alpha (Peg-IFNα), an injectable innate immune protein, is still used to treat chronically HBV-infected patients, despite its poor tolerability. Peg-IFNα has the advantage over nucleos(t)ide analogues (NAs) to be administrated in finite regimen and to lead to a higher HBsAg loss rate. Yet it would be interesting to improve the efficacy (i.e. while decreasing doses), or replace, this old medicine by novel small molecules/stimulators able to engage innate immune receptors in both HBV replicating hepatocytes and relevant innate immune cells. We have previously identified the Toll-Like-Receptor (TLR)-2 agonist Pam3CSK4 as such a potential novel immune stimulator. The aim of this study was to gain insights on the antiviral mechanisms of action of this agonist in in vitro cultivated human hepatocytes. We used in vitro models of HBV-infected cells, based on both primary human hepatocytes (PHH) and the non-transformed HepaRG cell line to investigate the MoA of Pam3SCK4 and identify relevant combinations with other approved or investigational drugs. We exhaustively described the inhibitory anti-HBV phenotypes induced by Pam3CSK4, which include a strong decrease in HBV RNA production (inhibition of synthesis and acceleration of decay) and cccDNA levels. We confirmed the long-lasting anti-HBV activity of this agonist, better described the kinetics of antiviral events, and demonstrated the specificity of action through the TLR1/2- NF-κB canonical-pathway. Moreover, we found that FEN-1 could be involved in the regulation and inhibitory phenotype on cccDNA levels. Finally, we identified the combination of Pam3CSK4 with IFNα or an investigational kinase inhibitor (called 1C8) as valuable strategies to reduce cccDNA levels and obtain a long-lasting anti-HBV effect in vitro. TLR2 agonists represent possible assets to improve the rate of HBV cure in patients. Further evaluations, including regulatory toxicity studies, are warranted to move toward clinical trials. •Pam3CSK4, a TLR2 agonist, is a potent anti-HBV agents.•Pam3CSK4 inhibits RNA accumulation by both impairing HBV transcription and RNA stability.•Pam3CSK4 decreases also cccDNA level via a FEN-1-dependent mechanism.•As a result, Pam3CSK4 has a long lasting effect.•Pam3CSK4 can be combined to other approved and investigational drugs.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0166-3542 1872-9096
DOI:	10.1016/j.antiviral.2022.105386