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Interaction between Toll-Like Receptor 9-CpG Oligodeoxynucleotides and Hepatitis B Virus Virions Leads to Entry Inhibition in Hepatocytes and Reduction of Alpha Interferon Production by Plasmacytoid Dendritic Cells

Abstract : We previously reported that Toll-like receptor 9 (TLR9)-CpG oligonucleo-tides could inhibit the establishment of hepatitis B virus (HBV) infections in hepato-cytes. Our aim was to uncover the underlying mechanisms of this inhibition. HepaRG cells, RPMI-B lymphoblastoma cells, and primary plasmacytoid dendritic cells (pDCs) exposed to HBV and TLR9 ligands/agonists in various configurations were used. We observed an inhibition of HBV infection upon TLR9 stimulations only when agonist was applied during inoculation. This inhibition was independent of interleukin-6 (IL-6)/interferon-inducible protein 10 (IP-10) production as well as of TLR9 expression in hepatocytes. We further demonstrated an entry inhibition mechanism by showing a noncovalent binding of TLR9 agonist to HBV particles. Besides inhibiting HBV entry into hepatocytes, this biophysical interaction between HBV virions and TLR9 agonist was responsible for a reduction of alpha interferon (IFN-) expression by pDCs. Interestingly , subviral particles composed of only HBsAg were able to genuinely inhibit the TLR9 pathway, without titrating TLR9 ligands. To conclude, our data suggest that synthetic TLR9-CpG oligonucleotides can strongly inhibit HBV entry by " coating " HBV virions and thereby preventing their interaction with cellular receptor. This titration effect of TLR9 agonist is also artifactually responsible for the inhibition of TLR9 engagement in pDCs, whereas a genuine inhibition of this innate pathway was confirmed with HBsAg subviral particles. H epatitis B virus (HBV) chronically infects 240 million people worldwide and represents one of the major etiologies for cirrhosis and hepatocellular carcinoma (1, 2). The progression rate of chronicity is tightly linked with the maturity of the immune system, since 90 to 95% of infected newborns become chronic carriers, whereas only 5 to 10% of adults do (3). As HBV long-term persistence is characterized by subversion of both innate and adaptive immunity (4, 5), a better understanding of the underlying cellular and molecular mechanisms of this escape should help in defining new therapeutic strategies to reactivate the host immune system and control viral replication. Current front-line therapies include the use of nucleoside analogues to specifically inhibit viral reverse transcription and/or pegylated interferon alpha 2a or 2b (Peg-IFN
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Submitted on : Friday, April 6, 2018 - 11:44:23 AM
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Ludovic Aillot, Marc Bonnin, Malika Ait-Goughoulte, Nathalie Bendriss-Vermare, Sarah Maadadi, et al.. Interaction between Toll-Like Receptor 9-CpG Oligodeoxynucleotides and Hepatitis B Virus Virions Leads to Entry Inhibition in Hepatocytes and Reduction of Alpha Interferon Production by Plasmacytoid Dendritic Cells. Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2018, 62 (4), pp.1741 - 1758. ⟨10.1128/AAC.01741-17⟩. ⟨inserm-01760408⟩

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