Vc9Vd2 T-cells are involved in host response to many chronic viral infections, including HCV. As observed in other chronic infection such as HIV, a KRX-0401 decrease of peripheral Vc9Vd2 T cell subset was observed associated to HCV infection. Activated Vc9Vd2 T lymphocytes were found able to inhibit subgenomic HCV replication, and this effect was mediated mainly by IFN-c release. A role of recombinant IFN-c on subgenomic HCV replication was also described. Moreover, several studies showed that the combination of recombinant IFN-c and IFN-a resulted in a strongly enhanced antiviral activity in the HCV replicon model, opening the way to new combined treatment approaches. Thus, IFN-c induced by Vc9Vd2 T-cell stimulation could enhance standard treatment effectiveness. In this work, phenotype and function of Vc9Vd2 T-cells were analyzed during chronic HCV infection, evaluating possible strategies aimed to improve their effector response. This approach was validated in vivo in a non-human primate model. Main aim of our work was to study the effects of chronic HCV infection on Vc9Vd2 T-cell phenotype and function, and on possible strategies aimed to improve their effector activity. Chronic HCV infection induced a slight but significant decrease in the frequency of Vc9Vd2 T-cells. An increased liver tissue compartmentalization of these cells may represent an additional factor. Differentiation and activation profile analysis of Vc9Vd2 T-cells showed an increase in circulating effector and activated cells. These data may be explained in the context of a chronic infection leading to a persistent stimulation of immune cells, driving their activation and differentiation. In our patients, no correlation was found between Vc9Vd2 T-cells dysfunction and any clinical parameter. Vc9Vd2 T-cells play a pivotal role in viral infections, for their ability to mediate broad antiviral and immunomodulating activities. Specifically, antiviral role of activated Vc9Vd2 T-cells, mainly mediated by IFN-c release, has been demonstrated for several viruses such as coronavirus, orthopoxvirus, HIV, and HCV. In our work, a severe functional inability of Vc9Vd2 T-cells to produce IFN-c was shown in HCV patients, independently from viral load and genotype. Such as DC and NK cells, that could be associated to adaptive immune response dysfunction and/or exhaustion. In this context, a complex network of different signals can act to induce immune cell exhaustion, such as chronic inflammation, persistent antigen stimulation, and/or direct viral effects. Chronic inflammation and persistent antigen stimulation, as observed during HIV infection, may result in Vc9Vd2 T-cell exhaustion and anergy through activation-induced cell death, or through a decrease in Vc9Vd2 T-cells response by down-modulating CD3-j chain expression. Finally, although controversial, a possible direct HCV-driven inhibition of NK cell function through HCVE2/CD81 binding has been reported. Interestingly, CD81 expression by cd T-cells was previously reported. A study aimed to define cellular and molecular mechanisms involved in Vc9Vd2 T-cells exhaustion during chronic HCV infection may be useful to evaluate possible strategies to restore their activity. The main result of our work is the demonstration that Vc9Vd2 T-cell function may be improved by IFN-a both in HD and in HCV-infected patients.