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

Immunomodulators that induce local endogenous interferon-alpha (IFN-alpha) 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-alpha 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 administered in vitro to pDCs purified from cHCV patients and from normal uninfected donors and their responses compared in terms of not only IFN-alpha production but also the global expression of other cytokines and phenotypic maturation. Plasmacytoid DCs from uninfected donors produced substantial levels of IFN-alpha in response to three of the four agonists and yet only one TLR9 agonist, a class C CpG oligodeoxynucleotide (ODN), induced robust IFN-alpha 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-alpha production by pDCs from cHCV donors. Nonetheless, a class C CpG ODN successfully induced robust IFN-alpha production, suggesting that this class of TLR9 agonist may have utility as a future immunotherapeutic for the treatment of chronic HCV infection.