A class C CpG toll‐like receptor 9 agonist successfully induces robust interferon‐alpha production by plasmacytoid dendritic cells from patients chronically infected with hepatitis C

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Abstract
Summary. Immunomodulators that induce local endogenous interferon‐alpha (IFN‐α) production by plasmacytoid dendritic cells (pDCs) may offer new strategies for the treatment of patients chronically infected with the hepatitis C virus (HCV). However, such an approach may be compromised if reports are true that IFN‐α production by pDCs from patients with chronic HCV (cHCV) is profoundly impaired. To address the question of pDC dysfunction in cHCV more definitively, in the present study a panel of four prototypic synthetic agonists of toll‐like receptor 7 (TLR7) or TLR9 were administeredin vitroto pDCs purified from cHCV patients and from normal uninfected donors and their responses compared in terms of not only IFN‐α production but also the global expression of other cytokines and phenotypic maturation. Plasmacytoid DCs from uninfected donors produced substantial levels of IFN‐α in response to three of the four agonists and yet only one TLR9 agonist, a class C CpG oligodeoxynucleotide (ODN), induced robust IFN‐α production by pDCs from cHCV patients. Proinflammatory cytokine production and phenotypic maturation in response to all four agonists was equivalent in infected and uninfected pDCs. These data point to a profound but selective defect in IFN‐α production by pDCs from cHCV donors. Nonetheless, a class C CpG ODN successfully induced robust IFN‐α production, suggesting that this class of TLR9 agonist may have utility as a future immunotherapeutic for the treatment of chronic HCV infection.

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