Early IL-10 Predominant Responses Are Associated With Progression to Chronic Hepatitis C Virus Infection in Injecting Drug Users

J. K. Flynn; G. J. Dore; M. Hellard; B. Yeung; W. D. Rawlinson; P. A. White; J. M. Kaldor; A. R. Lloyd; R. A. Ffrench

Disclosures

J Viral Hepat. 2011;18(8):549-561. 

In This Article

Abstract and Introduction

Abstract

The critical events in clearance or persistence of hepatitis C virus (HCV) infection are unknown but likely to be determined early in acute infection. Type 1 and type 2 cytokine production was assessed by HCV peptide ELISpot and multiplex in vitro cytokine production assays in longitudinally collected samples from 20 untreated participants enrolled in the Australian Trial in Acute Hepatitis C (ATAHC); a prospective cohort of acute HCV infection (77% injecting drug users, IDU). Significantly higher interleukin-10 (IL-10) production (P = 0.048), in the relative absence of interferon-gamma (IFN-γ) and IL-2 production, was present early in HCV infection in those who progressed to chronic infection. In contrast, viral clearance was associated with a greater magnitude and broader specificity of IFN-γ (magnitude P < 0.001, breadth P = 0.004) and IL-2 responses, in the relative absence of IL-10. Early IL-10 production was correlated with higher HCV RNA level at baseline (P = 0.046) and week 12 (P = 0.018), while IFN-γ and IL-2 production was inversely correlated with HCV RNA level at baseline (IFN-γP = 0.020, IL-2 P = 0.050) and week 48 (IFN-γP = 0.045, IL-2 P = 0.026). Intracellular staining (ICS) indicated the HCV-specific IFN-γ response was primarily from CD8+ T cells and NK cells, whereas IL-10 production was predominantly from monocytes, with a subset of IL-10 producing CD8+ T cells present only in those who progressed to chronic infection. IL-10, an immunoregulatory cytokine, appears to play a key role in progression to chronic HCV infection.

Introduction

Primary HCV infection is asymptomatic in the majority of cases, with 50–80% of individuals developing chronic infection.[1] The largely asymptomatic course of acute HCV infection combined with the marginalized nature of those individuals at greatest risk of HCV (IDU)[1] has limited the number of studies examining the early natural history and cellular immune responses of HCV infection.[2]

Clearance of HCV has been associated with early, multi-specific and sustained CD4+ [3–6] and CD8+ [7–9] responses directed against HCV epitopes,[10–12] and depletion of either CD4+ or CD8+ cells in the chimpanzee model promoted viral persistence.[7,13,14] Studies of chronic HCV infection have demonstrated a low frequency of HCV-specific CD4+ and CD8+ cells in both the peripheral blood and liver.[4] By contrast, no clear correlation has been found as yet between anti-HCV humoral responses and viral clearance.[15–17]

The innate immune response is a key component in the activation and maintenance of antiviral immunity, through induction of cytokines and initiation of the adaptive immune response. IFNs, in particular, have been shown to play a critical role in response to viral infections. Recently, clearance of HCV has been linked to genetic variation in IL-28B for both spontaneous[18] and treatment-induced clearance.[19,20] Polymorphisms approximately three kilobases upstream of the IL-28B gene, which encodes IFN-λ-3, have been associated with a 2-fold difference in response to HCV treatment[20] and spontaneous viral clearance.[18] In addition, IL-28A (IFN-λ-2) has been shown to promote antiviral activity by suppressing HCV IRES-mediated translation.[21] Type III IFNs (IL-29, IL-28A, IL-28B) share structural similarity with the IL-10 family of cytokines and share functional characteristics with type I IFNs as they signal through the JAK-STAT pathway and are induced by viral infections. Several HCV proteins, however, have been shown to impair the induction of type 1 IFNs, which then suppresses or delays subsequent adaptive T-cell responses critical for viral clearance.[22]

Helper CD4+ T cells are important for the control of viremia by promoting the effector function of virus-specific CD8+ T cells, particularly via IL-2 production.[23,24] For instance, Missale et al. (1996) detected higher magnitude HCV-specific T-cell responses in those with viral clearance compared to viral persistence,[25] suggesting the strength and timing of the T cell response is critical in determining the outcome of infection. Thus, functional impairment, suppression or deletion of antigen-specific T cells appears to be a key determinant of progression to chronicity.[11,26,27]

During persistent viral infections, specific T cells can become functionally inert, incapable of cytotoxicity and producing IL-2 or IFN-γ,[28,29] described as the 'stunned' phenotype in HCV infection.[4] Interference in the priming environment in HCV infection can reduce the effectiveness of the adaptive immune response, as low IL-2 concentrations caused expansion of memory cells, devoid of effector functions, while higher IL-2 concentrations during priming led to fully differentiated effector CD8+ T cells.[30]

The importance of the cytokine milieu in determining viral clearance has been emphasized by studies using the murine LCMV model; early and high-level IL-10 production was associated with viral persistence.[31,32] In this context, excess IL-10 has the ability to suppress cytokine production and proliferation by CD4+ and CD8+ T cells and to alter the function of antigen presenting cells.[33–35]

The objective of this study was to analyse the effect of recent HCV infection on the induction of effective cellular immune responses in a cohort where the majority of subjects were IDU. The hypothesis was that the type and level of key cytokines produced early in HCV infection is a critical determinant of viral persistence. This study demonstrates that early IL-10 predominant responses are found in those that progress to chronic HCV infection.

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