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

Mark A A Claassen,André Boonstra,Harry L A Janssen,Duygu Turgut,Zwier M A Groothuismink,Robert J De Knegt

doi:10.1371/journal.pone.0049389

Abstract

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-β and regulatory T-cells and the impact of pegylated interferon-alpha and ribavirin (PegIFN-α/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-α/ribavirin. Prior to treatment, IL-10 mediated suppression of HCV-specific IFN-γ 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-α/ribavirin therapy, negative regulation of especially HCV-specific IFN-γ production by TGF-β 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.

Highlights

In the vast majority of patients, the hepatitis C virus (HCV) causes chronic infection with viral replication primarily in the liver
Despite the fact that HCV-specific T-cell responses were weak or undetectable, up to 100 fold stronger CMV-specific T-cell proliferation was detected in Peripheral blood mononuclear cells (PBMC) of 40 out of 43 chronic HCV patients (Figure 1B)
This study establishes that the regulation by IL-10, TGF-b and Treg of dysfunctional HCV-specific immunity in chronic HCV patients is highly heterogeneous

Summary

Introduction

In the vast majority of patients, the hepatitis C virus (HCV) causes chronic infection with viral replication primarily in the liver. Treg in blood have been shown to suppress both HCV-specific proliferation and IFN-c production by CD4+ and CD8+ T-cells [10,11,12,13,14]. It has been suggested that Treg, at least partially, control chronic liver inflammation, with higher Treg suppressive capacity in patients with lower serum alanine transaminase (ALT) levels [11]. Other studies have shown that blocking IL-10 or TGF-b can enhance HCV-specific T-cell proliferation and IFN-c production [15,16,17,18,19]. Serum IL-10 and TGF-b levels were enhanced in HCV-infected patients as compared to control individuals, and augmented production of these inhibitory cytokines by monocytes and T-cells has been described for HCV-infected patients [15,17,18,19,20,21,22]

Methods

Results

Conclusion