What is disrupting IFN-alpha's antiviral activity?

Despite advances in treatment strategies for hepatitis C virus (HCV), a significant proportion of patients fail to achieve viral clearance following treatment with pegylated interferon (IFN)-alpha plus ribavirin. Many of these individuals show elevated levels of tumor necrosis factor (TNF)-alpha compared with normal controls, and recent data have implicated this cytokine in the negative regulation of IFN-alpha. Although a therapeutic opportunity for TNF-alpha antagonists might exist for reducing inflammation in chronic HCV disease, further exploration is required to identify the key mediators of responsiveness to IFN-alpha. In particular, the interplay should be clarified between host response factors [e.g. IFN-alpha, IFN-gamma, suppressor of cytokine signaling (SOCS), TNF-alpha and others] and pathogen-associated molecular patterns [PAMPs, e.g. lipopolysaccharide (LPS) and CpG DNA] in HCV disease; this information might guide future therapies aimed at improving IFN-alpha responsiveness.