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Negative regulation of hepatitis C virus specific immunity is highly heterogeneous and modulated by pegylated interferon-alpha/ribavirin therapy.

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

SUBMITTER: Claassen MA

PROVIDER: S-EPMC3493527 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Negative regulation of hepatitis C virus specific immunity is highly heterogeneous and modulated by pegylated interferon-alpha/ribavirin therapy.

Claassen Mark A A MA de Knegt Robert J RJ Turgut Duygu D Groothuismink Zwier M A ZM Janssen Harry L A HL Boonstra André A

PloS one 20121108 11

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 befo ...[more]

PMID: 23145169

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Project description:To investigate the safety and efficacy of a Hansenula-derived PEGylated (polyethylene glycol) interferon (IFN)-alpha-2a (Reiferon Retard) plus ribavirin customized regimen in treatment-naïve and previously treated (non-responders and relapsers) Egyptian children with chronic hepatitis C infection.Forty-six children with chronic hepatitis C virus (HCV) infection were selected from three tertiary pediatric hepatology centers. Clinical and laboratory evaluations were undertaken. Quantitative polymerase chain reaction (PCR) for HCV-RNA was performed before starting treatment, and again at 4, 12, 24, 48, 72 wk during treatment and 6 mo after treatment cessation. All patients were assigned to receive a weekly subcutaneous injection of PEG-IFN-alpha-2a plus daily oral ribavirin for 12 wk. Thirty-four patients were treatment-naïve and 12 had a previous treatment trial. Patients were then divided according to PCR results into two groups. Group?I?included patients who continued treatment on a weekly basis (7-d schedule), while group II included patients who continued treatment on a 5-d schedule. Patients from either group who were PCR-negative at week 48, but had at least one PCR-positive test during therapy, were assigned to have an extended treatment course up to 72 wk. The occurrence of adverse effects was assessed during treatment and follow up. The study was registered at www.ClinicalTrials.gov (NCT02027493).Only 11 out of 46 (23.9%) patients showed a sustained virological response (SVR), two patients were responders at the end of treatment; however, they were lost to follow up at 6 mo post treatment. Breakthrough was seen in 18 (39.1%) patients, one patient (2.17%) showed relapse and 14 (30.4%) were non-responders. Male gender, short duration of infection, low viral load, mild activity, and mild fibrosis were the factors related to a better response. On the other hand, patients with high viral load and absence of fibrosis failed to respond to treatment. Before treatment, liver transaminases were elevated. After commencing treatment, they were normalized in all patients at week 4 and were maintained normal in responders till the end of treatment, while they increased again significantly in non-responders (P = 0.007 and 0.003 at week 24 and 72 respectively). The 5-d schedule did not affect the response rate (1/17 had SVR). Treatment duration (whether 48 wk or extended course to 72 wk) gave similar response rates (9/36 vs 2/8 respectively; P = 0.49). Type of previous treatment (short acting IFN vs PEG-IFN) did not affect the response to retreatment. On the other hand, SVR was significantly higher in previous relapsers than in previous non-responders (P = 0.039). Only mild reversible adverse effects were observed and children tolerated the treatment well.Reiferon Retard plus ribavirin combined therapy was safe. Our customized regimen did not influence SVR rates. Further trials on larger numbers of patients are warranted.

Project description:BackgroundRecent studies of CH-C patients have demonstrated a strong association between IL28B CC genotype and sustained virologic response (SVR) after PEG-IFN/RBV treatment. We aimed to assess whether IL28B alleles rs12979860 genotype influences gene expression in response to PEG-IFN/RBV in CH-C patients.MethodsClinical data and gene expression data were available for 56 patients treated with PEG-IFN/RBV. Whole blood was used to determine IL28B genotypes. Differential expression of 153 human genes was assessed for each treatment time point (Days: 0, 1, 7, 28, 56) and was correlated with IL28B genotype (IL28B C/C or non-C/C) over the course of the PEG-IFN/RBV treatment. Genes with statistically significant changes in their expression at each time point were used as an input for pathway analysis using KEGG Pathway Painter (KPP). Pathways were ranked based on number of gene involved separately per each study cohort.ResultsThe most striking difference between the response patterns of patients with IL28B C/C and T* genotypes during treatment, across all pathways, is a sustained pattern of treatment-induced gene expression in patients carrying IL28B C/C. In the case of IL28B T* genotype, pre-activation of genes, the lack of sustained pattern of gene expression or a combination of both were observed. This observation could potentially provide an explanation for the lower rate of SVR observed in these patients. Additionally, when the lists of IL28B genotype-specific genes which were differentially expressed in patients without SVR were compared at their baseline, IRF2 and SOCS1 genes were down-regulated regardless of patients' IL28B genotype. Furthermore, our data suggest that CH-C patients who do not have the SOCS1 gene silenced have a better chance of achieving SVR. Our observations suggest that the action of SOCS1 is independent of IL28B genotype.ConclusionsIL28B CC genotype patients with CH-C show a sustained treatment-induced gene expression profile which is not seen in non-CC genotype patients. Silencing of SOCS1 is a negative and independent predictor of SVR. These data may provide some mechanistic explanation for higher rate of SVR in IL28B CC patients who are treated with PEG-IFN/RBV.

Dataset Information

Negative regulation of hepatitis C virus specific immunity is highly heterogeneous and modulated by pegylated interferon-alpha/ribavirin therapy.

Publications

Negative regulation of hepatitis C virus specific immunity is highly heterogeneous and modulated by pegylated interferon-alpha/ribavirin therapy.

Similar Datasets

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