Interferon-α Improves Phosphoantigen-Induced Vγ9Vδ2 T-Cells Interferon-γ Production during Chronic HCV Infection

Eleonora Cimini,Giulia Berno,Ubaldo Visco Comandini,Cristiana Gioia,Chrysoula Vlassi,Federico Martini,Alessandra Sacchi,Gianpiero D’Offizi,Helene Sicard,Cécile Bonnafous,Maria Rosaria Capobianchi,Eleonora Lalle,Chiara Agrati,Veronica Bordoni,Eui-Cheol Shin

doi:10.1371/journal.pone.0037014

Eleonora Cimini, Giulia Berno + Show 13 more

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https://doi.org/10.1371/journal.pone.0037014

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Abstract

In chronic HCV infection, treatment failure and defective host immune response highly demand improved therapy strategies. Vγ9Vδ2 T-cells may inhibit HCV replication in vitro through IFN-γ release after Phosphoantigen (PhAg) stimulation. The aim of our work was to analyze Vγ9Vδ2 T-cell functionality during chronic HCV infection, studying the role of IFN-α on their function capability. IFN-γ production by Vγ9Vδ2 T-cells was analyzed in vitro in 24 HCV-infected patients and 35 healthy donors (HD) after PhAg stimulation with or without IFN-α. The effect of in vivo PhAg/IFN-α administration on plasma IFN-γ levels was analyzed in M. fascicularis monkeys. A quantitative analysis of IFN-γ mRNA level and stability in Vγ9Vδ2 T-cells was also evaluated. During chronic HCV infection, Vγ9Vδ2 T-cells showed an effector/activated phenotype and were significantly impaired in IFN-γ production. Interestingly, IFN-α was able to improve their IFN-γ response to PhAg both in vitro in HD and HCV-infected patients, and in vivo in Macaca fascicularis primates. Finally, IFN-α increased IFN-γ-mRNA transcription and stability in PhAg-activated Vγ9Vδ2 T-cells. Altogether our results show a functional impairment of Vγ9Vδ2 T-cells during chronic HCV infection that can be partially restored by using IFN-α. A study aimed to evaluate the antiviral impact of PhAg/IFN-α combination may provide new insight in designing possible combined strategies to improve HCV infection treatment outcome.

Highlights

Most Hepatitis C virus (HCV) infections evolve in persistent infection, which may progress to fibrosis, cirrhosis, liver failure or even hepatocellular carcinoma [1]
Vc9Vd2 T-cell subsets were analyzed in 24 HCV-infected patients (HCV), naıve to treatment, and compared with 35 healthy donors (HD)
Vc9Vd2 T-cell differentiation profile showed a significant increase in Vc9Vd2 effector cells (CD45RA+CD27-) in HCV patients [HCV: median 6.5 (IQR: 3.5–13.0) vs. HD: 2.2 (0.7–7.2), p = 0.0214], suggesting that chronic HCV infection induced Vc9Vd2 T-cell differentiation toward effector functions (Figure 1A–B)

Summary

Introduction

Most Hepatitis C virus (HCV) infections evolve in persistent infection, which may progress to fibrosis, cirrhosis, liver failure or even hepatocellular carcinoma [1]. Current standard therapy is based on a combination of pegylated (PEG)-IFN-a and ribavirin (RBV) and treatment response may be influenced by several virusrelated factors such as HCV genotype and baseline titer of HCV RNA [2,3]. A sustained virological response (SVR) occurs in approximately 80% of patients infected with HCV genotypes 2 or 3, and in approximately 45% for genotypes 1 or 4 [4]. New antiviral strategies are currently in development for HCV infection and include drugs targeting key viral enzymes such as NS3-4A and the NS5B RNA-dependent RNA polymerase [5]. The use of these new antivirals seems associated to the selection of drug-resistant HCV variants, resulting in viral breakthrough. A combination between antivirals and standard treatment with IFNa and RBV is necessary [3,6]

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