Respiratory syncytial virus co-opts hypoxia-inducible factor-1α-mediated glycolysis to favor the production of infectious virus

Glycolysis, a series of oxidative reactions used to metabolize glucose and provide energy to host cells, is also required for respiratory syncytial virus (RSV) infection. However, the role of glycolysis during RSV infection and its underlying molecular mechanisms remain to be further explored. In this study, we investigated the function of hypoxia-inducible factor (HIF)-1 alpha-mediated glycolysis in HEp-2 cells and mouse models during RSV infection. The results showed that RSV infection activated the insulin receptor (IR)-PI3K-Akt axis, upregulated the translation and activity of HIF-1 alpha, increased the expression of glucose transporters (Glut1, Glut3, and Glut4), hexokinase (HK) 1 and 2, and platelet-type phosphofructokinase (PFKP), and promoted glucose uptake and glycolysis. In addition, mitochondrial damage induced by RSV resulted in the generation of large amounts of reactive oxygen species (ROS) in infected cells, which contributed to the stabilization and activation of HIF-1 alpha. An energy map of the glycolytic ATP production rate (Glyco-ATP) versus the mitochondrial ATP production rate (mito-ATP) confirmed a switch from oxidative phosphorylation (OXPHOS) to glycolysis. Inhibition of IR-PI3K-Akt signaling, ROS, or HIF-1 alpha effectively reversed the RSV-induced increase in glycolysis by blocking HIF-1 alpha activation. Importantly, HIF-1 alpha-mediated glycolysis provided energy for the production of progeny RSV virions. The production of infectious virions was nearly abolished after knocking down HIF-1 alpha. PX-478, an orally active HIF-1 alpha inhibitor, effectively inhibited RSV infection in vivo. Collectively, these results indicate the role of HIF-1 alpha-mediated glycolysis in RSV infection and highlight HIF-1 alpha as a potential target for anti-RSV drug development.