bioRxiv. 2023 Aug 17. pii: 2023.08.15.553422. [Epub ahead of print]
Hypoxia-inducible-factors (HIF) are transcription factors that regulate cellular adaptation to hypoxic conditions, enabling cells to survive in low-oxygen environments. Viruses have evolved to stabilize this pathway to promote successful viral infection, therefore modulation of HIFs could represent a novel antiviral strategy. In previous in vitro studies, we demonstrate respiratory syncytial virus (RSV), a leading cause of respiratory illness, to stabilize HIFs under normoxic conditions, with inhibition of HIF-1α resulting in reduced viral replication. Despite several HIF modulating compounds being tested/approved for use in other non-infectious models, little is known about their efficacy against respiratory viruses using relevant animal models. This study aimed to characterize the disease modulating properties and antiviral potential of anti-HIF-1α (PX478) and anti-HIF-2α (PT2385) in RSV-infected BALB/c mice. We found inhibition of HIF-1α to worsen clinical disease parameters, while simultaneously improving airway function. Additionally, anti-HIF-1α results in significantly reduced viral titer at early and peak time points of RSV replication, followed by a loss in viral clearance when given every day, but not every-other-day. In contrast, inhibition of HIF-2α was associated with improved clinical parameters, with no changes in airway function, and amelioration of interstitial pneumonia. Furthermore, anti-HIF-2α reduced early and peak lung viral replication, with no impaired viral clearance. Analysis of lung cells found significant modification in the T cell compartment that correlated with changes in lung pathology and viral titers in response to each HIF inhibitor administration. These data underscore the complex role of HIFs in RSV infection and highlight the need for careful therapeutic consideration.Importance: The pharmacological use of HIF therapeutics has largely been investigated with various models of cancer, autoimmunity, and non-infectious lung damage. The safety and success of these compounds is emphasized by their use in several phase-4 clinical trials. Since the early 2000s, numerous studies have demonstrated the antiviral potential of HIF inhibitors in epithelial cell lines, however, there are no studies characterizing the therapeutic outcomes of suppressing HIF during a viral respiratory infection in a relevant animal model. With the growing interest in drug repositioning, our research emphasizes the importance of testing approved or abandoned therapeutics under the new conditions in a complex biological model encompassing both the epithelial and immune compartments. Moreover, the current study uncovers a novel role of HIFs in the pathogenesis of RSV disease. These data collectively demonstrate a key mechanism in immune regulation during RSV infection that can further therapeutic development.