HIF-1α modulates core metabolism and virus replication in primary airway epithelial cells infected with respiratory syncytial virus

Metabolic reprogramming of host cells is key to the foundation of a successful viral infection. Hypoxia inducible factors (HIFs) mediate oxygen utilization by regulating cellular metabolism and redox homeostasis. Under normoxic conditions, HIF proteins are synthesized and subsequently degraded following ubiquitination to allow for normal metabolic activities. Recent studies suggest that respiratory syncytial virus (RSV) has the ability to induce HIF-1α stabilization and accumulation through non-hypoxic mechanisms. This makes the HIF pathway a potential avenue of approach for RSV therapeutic development. Using a model of primary human small alveolar epithelial cells, we demonstrate RSV infections to greatly alter cellular metabolism in favor of the glycolytic and pentose phosphate pathways. Additionally, we show RSV infections to stabilize HIF-1α and HIF-2α expression in these cells. Inhibition of HIF-1α, but not HIF-2α, was found to significantly reduce RSV replication as well as the glycolytic pathway, as measured by the expression of hexokinase II. Our study contributes to the understanding of RSV-mediated changes to cellular metabolism and supports further investigation into anti-HIF-1α therapeutics for RSV infections.