Beta interferon regulation of glucose metabolism is PI3K/Akt dependent and important for antiviral activity against coxsackievirus B3

An effective type I interferon (IFN)-mediated immune response requires the rapid expression of antiviral proteins that are necessary to inhibit viral replication and virus spread. We provide evidence that IFN-β regulates metabolic events important for the induction of a rapid antiviral response: IFN-β decreases the phosphorylation of AMP-activated protein kinase (AMPK), coincident with an increase in intracellular ATP. Our studies reveal a biphasic IFN-β-inducible uptake of glucose by cells, mediated by phosphatidylinositol 3-kinase (PI3K)/Akt, and IFN-β-inducible regulation of GLUT4 translocation to the cell surface. Additionally, we provide evidence that IFN-β-regulated glycolytic metabolism is important for the acute induction of an antiviral response during infection with coxsackievirus B3 (CVB3). Last, we demonstrate that the antidiabetic drug metformin enhances the antiviral potency of IFN-β against CVB3 both in vitro and in vivo. Taken together, these findings highlight an important role for IFN-β in modulating glucose metabolism during a virus infection and suggest that the use of metformin in combination with IFN-β during acute virus infection may result in enhanced antiviral responses.