T-705 (Favipiravir) suppresses tumor necrosis factor a production in response to influenza virus infection: A beneficial feature of T-705 as an anti-influenza drug

Influenza virus infection induces the production of various cytokines, which play important roles in the pathogenesis of infection. Among the cytokines induced by influenza, tumor necrosis factor a (TNF-alpha) production has been correlated with the severity of lung lesions. We investigated the effects of T-705 (Favipiravir, 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) on cytokine production due to influenza virus infection in vitro and in vivo, compared with oseltamivir or GS 4071, an active form of oseltamivir. TNF-alpha production in mouse macrophage-derived P388D1 cells infected with the influenza virus was lower following treatment with T-705 at concentrations of 0.3 to 100 mu g/ml than treatment with GS 4071 at the same concentrations. The effect of treatment with T-705 on the cytokine production induced by the influenza virus infection was investigated in mouse influenza virus infection model. At 48 h post-infection (p.i.) T-705 significantly suppressed the viral load in the lungs and TNF-alpha production in the airways of infected mice even when viral loads were high. Furthermore, T-705 suppressed only TNF-alpha production from the early phase of infection. In this study, T-705 showed the antiviral activity of reducing pulmonary viral load compared with oseltamivir, thereby suppressing the TNF-alpha production. This feature of T-705 is benefit against severe influenza infection.