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)-1α-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-1α, 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-1α. 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-1α effectively reversed the RSV-induced increase in glycolysis by blocking HIF-1α activation. Importantly, HIF-1α-mediated glycolysis provided energy for the production of progeny RSV virions. The production of infectious virions was nearly abolished after knocking down HIF-1α. PX-478, an orally active HIF-1α inhibitor, effectively inhibited RSV Infection in vivo. Collectively, these results indicate the role of HIF-1α-mediated glycolysis in RSV Infection and highlight HIF-1α as a potential target for anti-RSV drug development. IMPORTANCE Respiratory syncytial virus (RSV) is the leading etiological agent of lower respiratory tract illness. However, efficacious vaccines or Antiviral drugs for treating RSV infections are currently not available. Indeed, RSV depends on host cells to provide energy needed to produce progeny virions. Glycolysis is a series of oxidative reactions used to metabolize glucose and provide energy to host cells. Therefore, glycolysis may be helpful for RSV Infection. In this study, we show that RSV increases glycolysis by inducing the stabilization, transcription, translation, and activation of hypoxia-inducible factor (HIF)-1α in infected cells, which is important for the production of progeny RSV virions. This study contributes to understanding the molecular mechanism by which HIF-1α-mediated glycolysis controls RSV Infection and reveals an effective target for the development of highly efficient anti-RSV drugs.

HIF-1α; IR-PI3K-Akt signaling; ROS; glycolysis; mitochondria; respiratory syncytial virus.