Role of Hypoxia-Inducible Factors in Respiratory Syncytial Virus Infection-Associated Lung Disease

Hypoxia-inducible factors (HIFs) are transcription factors that enable cells to adapt to low-oxygen environments. Viruses can exploit this pathway to enhance infection, making HIF modulation a potential antiviral strategy. In previous in vitro studies, we found that respiratory syncytial virus (RSV) stabilizes HIFs under normoxic conditions with inhibition of HIF-1α reducing replication. Despite several HIF-modulating compounds being tested or approved in other non-infectious models, little is known about their efficacy against respiratory viruses in relevant animal models. This study aimed to characterize the disease-modulating properties and antiviral potential of HIF-1α (PX478) and HIF-2α PT2385 inhibitors in RSV-infected BALB/c mice. We found that the inhibition of HIF-1α worsened clinical disease parameters while simultaneously improving airway function. Blocking HIF-1α also significantly reduced peak RSV replication in the lung. In contrast, the inhibition of HIF-2α was associated with improved clinical parameters, no changes in airway function, and reduced viral replication following RSV infection. The analysis of lung cells found significant modification in the T-cell compartment that correlated with changes in lung pathology and viral titers for each HIF inhibitor. This study underscores the differential roles of HIF proteins in RSV infection and highlights the need for further characterization of compounds currently in use or under therapeutic consideration.