Journal Article

Direct antiviral properties of TLR ligands against HBV replication in immune-competent hepatocytes

Lucifora, Julie, Fusil, Floriane, Durantel, David, Michelet, Maud, Salvetti, Anna, Ollivier, Anaïs, Zoulim, Fabien, Ait-Goughoulte, Malika, Rivoire, Michel, Aillot, Ludovic, Cosset, François-Loïc, Dimier, Laura, Floriot, Océane, Daffis, Stéphane, Bonnin, Marc, Fletcher, Simon P., Maadadi, Sarah

2018

Overview

Current therapies for chronic hepatitis B virus (HBV) infections are effective at decreasing the viral load in serum, but do not lead to viral eradication. Recent studies highlighted the therapeutic or “adjuvant” potential of immune-modulators. Our aim was to explore the direct anti-HBV effect of Toll-Like-Receptors (TLR) agonists in hepatocytes. HBV-infected primary human hepatocytes (PHH) or differentiated HepaRG cells (dHepaRG) were treated with various TLR agonists. Amongst all TLR ligands tested, Pam3CSK4 (TLR1/2-ligand) and poly(I:C)-(HMW) (TLR3/MDA5-ligand) were the best at reducing all HBV parameters. No or little viral rebound was observed after treatment arrest, implying a long-lasting effect on cccDNA. We also tested Riboxxol that features improved TLR3 specificity compared to poly(I:C)-(HMW). This agonist demonstrated a potent antiviral effect in HBV-infected PHH. Whereas, poly(I:C)-(HMW) and Pam3CSK4 mainly induced the expression of classical genes from the interferon or NF-κB pathway respectively, Riboxxol had a mixed phenotype. Moreover, TLR2 and TLR3 ligands can activate hepatocytes and immune cells, as demonstrated by antiviral cytokines produced by stimulated hepatocytes and peripheral blood mononuclear cells. In conclusion, our data highlight the potential of innate immunity activation in the direct control of HBV replication in hepatocytes, and support the development of TLR-based antiviral strategies.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/106 / 13/95 / 14 / 38 / 38/22 / 631/154/1435/2417 / 631/326/596/1550 / Antiviral activity / Antiviral drugs / Hepatitis B / Hepatocytes / Human health and pathology / Humanities and Social Sciences / Hépatology and Gastroenterology / Immunology / Immunomodulation / Immunotherapy / Infectious diseases / Innate immunity / Interferon / Leukocytes (mononuclear) / Life Sciences / Ligands / multidisciplinary / NF-κB protein / Peripheral blood mononuclear cells / Phenotypes / Polyinosinic:polycytidylic acid / Replication / Science / Science (multidisciplinary) / TLR1 protein / TLR2 protein / TLR3 protein / Toll-like receptors