Abstract Oxygen-sensing mechanisms allow cells to adapt and respond to changes in cellular oxygen tension, including hypoxic conditions. Hypoxia-inducible factor (HIF) is a central mediator in this fundamental adaptive response, and has critical functions in normal and disease physiology. Viruses have been shown to manipulate HIFs during their life cycle to facilitate replication and invasion. Conversely, HIFs are also implicated in the development of the host immune system and response to viral infections. Here, we highlight the recent revelations of host-pathogen interactions that involve the hypoxic response pathway and the role of HIF in emerging viral infectious diseases, as well as discussing potential antiviral therapeutic strategies targeting the HIF signaling axis. Conclusion As the frequency of novel emerging viral infections increases, there is an urgent need to better understand the mechanisms surrounding host-pathogen interactions. Although recent studies have analyzed the role of hypoxia and HIF signaling in host immunity and in various states of infection, its involvement in viral pathogenesis remains largely unclear. Elucidating the function of HIF signaling in either facilitating or inhibiting viral replication could assist in the development of therapeutics. Furthermore, understanding the possible effect that hypoxia can exert on the immune response in both mild and severe infections may allow for more specialized treatment options for patients. https://insight.jci.org/articles/view/147190
