Abstract
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 administered in vitro to 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.
Highlights
The hepatitis C virus (HCV) is a blood-borne, hepatotrophic virus which establishes chronic HCV infection in up to 85% of cases
interferon alpha (IFN-a) promotes the development of a polarized antigen-specific type 1 T-cell response [6,7] thought to favour resolution of HCV infection [8] and plasmacytoid dendritic cells (pDCs)-derived IFN-a supports the induction of CD8+ T cell responses [9]
Plasmacytoid DCs circulate in the blood at low frequency and pDC numbers may be further reduced in chronic HCV (cHCV) infection [25,27]
Summary
The hepatitis C virus (HCV) is a blood-borne, hepatotrophic virus which establishes chronic HCV (cHCV) infection in up to 85% of cases. The mainstay of current therapies for cHCV is interferon alpha (IFN-a), a type 1 interferon typically administered as pegylated, single-species IFN-a2 in combination with the antiviral ribavirin. IFN-a promotes the development of a polarized antigen-specific type 1 T-cell response [6,7] thought to favour resolution of HCV infection [8] and pDC-derived IFN-a supports the induction of CD8+ T cell responses [9]. Combined pegylated IFNa2 ⁄ ribavirin therapy succeeds in only 42–46% of HCV genotype 1 infections and 76–80% of genotype 2 ⁄ 3 infections [2]. The raised systemic levels of IFN-a can lead to psychiatric and other adverse events necessitating premature cessation of treatment in approximately 10% of cases [10]. Alternative novel strategies for the treatment of cHCV are required
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