Blood Journal
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HCV glycoprotein E2 is a novel BDCA-2 ligand and acts as an inhibitor of IFN production by plasmacytoid dendritic cells

  1. Jonathan Florentin14,
  2. Besma Aouar14,
  3. Clélia Dental14,
  4. Christine Thumann5,
  5. Guylène Firaguay14,
  6. Francoise Gondois-Rey14,
  7. Vassili Soumelis6,
  8. Thomas F. Baumert5,
  9. Jacques A. Nunès14,
  10. Daniel Olive14,
  11. Ivan Hirsch14, and
  12. Ruzena Stranska14
  1. 1Inserm Unité Mixte de Recherche (UMR) 1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France;
  2. 2Institut Paoli-Calmettes, Marseille, France;
  3. 3Aix-Marseille Université, Marseille, France;
  4. 4Centre National de la Recherche Scientifique, UMR7258, Centre de Recherche en Cancérologie de Marseille, Marseille, France;
  5. 5Inserm UMR748, Université de Strasbourg, Institut de Virologie, Strasbourg, France; and
  6. 6Institut Curie, Paris, France


The elimination of hepatitis C virus (HCV) in > 50% of chronically infected patients by treatment with IFN-α suggests that plasmacytoid dendritic cells (pDCs), major producers of IFN-α, play an important role in the control of HCV infection. However, despite large amounts of Toll-like receptor 7-mediated IFN-α, produced by pDCs exposed to HCV-infected hepatocytes, HCV still replicates in infected liver. Here we show that HCV envelope glycoprotein E2 is a novel ligand of pDC C-type lectin immunoreceptors (CLRs), blood DC antigen 2 (BDCA-2) and DC-immunoreceptor (DCIR). HCV particles inhibit, via binding of E2 glycoprotein to CLRs, production of IFN-α and IFN-λ in pDCs exposed to HCV-infected hepatocytes, and induce in pDCs a rapid phosphorylation of Akt and Erk1/2, in a manner similar to the crosslinking of BDCA-2 or DCIR. Blocking of BDCA-2 and DCIR with Fab fragments of monoclonal antibodies preserves the capacity of pDCs to produce type I and III IFNs in the presence of HCV particles. Thus, negative interference of CLR signaling triggered by cell-free HCV particles with Toll-like receptor signaling triggered by cell-associated HCV results in the inhibition of the principal pDC function, production of IFN.

  • Submitted February 23, 2012.
  • Accepted September 26, 2012.
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