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

In chronic HCV infection, treatment failure and defective host immune response highly demand improved therapy strategies. V gamma 9V delta 2 T-cells may inhibit HCV replication in vitro through IFN-gamma release after Phosphoantigen (PhAg) stimulation. The aim of our work was to analyze V gamma 9V delta 2 T-cell functionality during chronic HCV infection, studying the role of IFN-alpha on their function capability. IFN-gamma production by Vc gamma V delta 2 T-cells was analyzed in vitro in 24 HCV-infected patients and 35 healthy donors (HD) after PhAg stimulation with or without IFN-alpha. The effect of in vivo PhAg/IFN-alpha administration on plasma IFN-gamma levels was analyzed in M. fascicularis monkeys. A quantitative analysis of IFN-gamma mRNA level and stability in V gamma 9V delta 2 T-cells was also evaluated. During chronic HCV infection, V gamma 9V delta 2 T-cells showed an effector/activated phenotype and were significantly impaired in IFN-gamma production. Interestingly, IFN-alpha was able to improve their IFN-gamma response to PhAg both in vitro in HD and HCV-infected patients, and in vivo in Macaca fascicularis primates. Finally, IFN-alpha increased IFN-gamma-mRNA transcription and stability in PhAg-activated V gamma 9V delta 2 T-cells. Altogether our results show a functional impairment of V gamma 9V delta 2 T-cells during chronic HCV infection that can be partially restored by using IFN-alpha. A study aimed to evaluate the antiviral impact of PhAg/IFN-alpha combination may provide new insight in designing possible combined strategies to improve HCV infection treatment outcome.