Negative Regulation of Hepatitis C Virus Specific Immunity Is Highly Heterogeneous and Modulated by Pegylated Interferon-Alpha/Ribavirin Therapy

Specific inhibitory mechanisms suppress the T-cell response against the hepatitis C virus (HCV) in chronically infected patients. However, the relative importance of suppression by IL-10, TGF-beta and regulatory T-cells and the impact of pegylated interferon-alpha and ribavirin (PegIFN-alpha/ribavirin) therapy on these inhibitory mechanisms are still unclear. We revealed that coregulation of the HCV-specific T-cell responses in blood of 43 chronic HCV patients showed a highly heterogeneous pattern before, during and after PegIFN-alpha/ribavirin. Prior to treatment, IL-10 mediated suppression of HCV-specific IFN-gamma production in therapy-naive chronic HCV patients was associated with higher HCV-RNA loads, which suggests that protective antiviral immunity is controlled by IL-10. In addition, as a consequence of PegIFN-alpha/ribavirin therapy, negative regulation of especially HCV-specific IFN-gamma production by TGF-beta and IL-10 changed dramatically. Our findings emphasize the importance of negative regulation for the dysfunctional HCV-specific immunity, which should be considered in the design of future immunomodulatory therapies. Citation: Claassen MAA, de Knegt RJ, Turgut D, Groothuismink ZMA, Janssen HLA, et al. (2012) Negative Regulation of Hepatitis C Virus Specific Immunity Is Highly Heterogeneous and Modulated by Pegylated Interferon-Alpha/Ribavirin Therapy. PLoS ONE 7(11): e49389. doi:10.1371/journal.pone.0049389