In vivo interferon-alpha/ribavirin treatment modulates Vγ9Vδ2 T-cell function during chronic HCV infection

In chronic hepatitis C virus (HCV) infection, treatment failure and defective host immune response highly demand improved therapy strategies. Vγ9Vδ2 T-cells represent a good target for HCV immunotherapy, since phosphoantigen (PhAg)-activated Vγ9Vδ2 T-lymphocytes are able to inhibit subgenomic HCV replication by interferon (IFN)-γ release. A profound impairment of IFN-γ production by Vγ9Vδ2 T-cells during chronic HCV infection was previously shown. Interestingly, in vitro IFN-α partially restored Vγ9Vδ2 T-cells responsiveness to PhAg, by stabilizing IFN-γ-mRNA. To verify how in vivo IFN-α/ribavirin (RBV) treatment could affect Vγ9Vδ2 T-cells phenotype and responsiveness to PhAg in HCV-infected patients, 10 subjects underwent a longitudinal study before and after treatment. IFN-α/RBV therapy did not significantly modify Vγ9Vδ2 T-cell numbers and differentiation profile. Interestingly, Vγ9Vδ2 T-cell responsiveness remained unmodified until 3 weeks of therapy, but dropped after 1 month, suggesting that repeated in vivo IFN-α administration in the absence of T-cell receptor (TCR)-mediated signals results in Vγ9Vδ2 T-cell anergy. The present work defines the window of possible application of combined strategies targeting Vγ9Vδ2 T-cells during chronic HCV infection; specifically, the first 3 weeks from the beginning of treatment may represent the optimal time to target Vγ9Vδ2 T-cells in vivo, since their function in terms of IFN-γ production is preserved.