Activation of V gamma 9V delta 2 T cells by non-peptidic antigens induces the inhibition of subgenomic HCV replication

Hepatitis C virus (HCV) has evolved complex strategies to evade host immune responses and establish chronic infection. Since human V gamma 9V delta 2 T lymphocytes play a critical role in the immune response against viruses, we analyzed their antiviral functions on Huh7 hepatoma cells carrying the subgenomic HCV replicon (Rep60 cells). In a transwell culture system, Rep60 cells were co-cultured with either PBMCs or highly purified gamma delta T cells stimulated by non-peptidic antigens. V gamma 9V delta 2 T cell activation was associated with a dramatic reduction of HCV RNA levels. Neutralizing antibodies targeting IFN-gamma revealed a critical role for this cytokine in the inhibition of HCV replication. Interestingly, drugs already in clinical use, such as Phosphostim and Zoledronate, known to activate gamma delta T cells, were shown to induce the inhibition of HCV replication mediated by V gamma 9V delta 2 T cells of HCV patients. Our data suggest that the therapeutic activation of V gamma 9V delta 2 T lymphocytes may represent an additional strategy to inhibit HCV replication and to restore a T(h)1-oriented immune response in HCV-infected patients.