Hypoxic and pharmacological activation of HIFs inhibits respiratory syncytial virus infection.
Respiratory syncytial virus (RSV) is a significant global healthcare problem, causing severe respiratory illness in young children and elderly individuals. The only approved prophylactic treatment is Palivizumab, an antibody to RSV Fusion protein, that has modest efficacy and can lead to resistance. There are no approved antiviral drugs, highlighting an urgent need for new therapies. Understanding the host pathways that define susceptibility to RSV infection and disease are essential for the design of new therapies. In this study, we identify a role for the hypoxic inducible factor (HIF) signalling to inhibit RSV infection. In RSV-infected mice, treatment with the clinically approved HIF prolyl-hydroxylase inhibitor, Daprodustat, reduced the frequency of virus infected pneumocytes and infectious virus in the lungs. We demonstrate that both hypoxia and the HIF prolyl-hydroxylase inhibitors reduce expression of the cellular RSV entry receptor nucleolin and inhibit RSV mediated cell-cell fusion. We identify a hypoxia-induced microRNA, miR-494, that regulates nucleolin expression. In RSV-infected mice, treatment with the clinically approved HIF prolyl-hydroxylase inhibitor, Daprodustat, reduced the frequency of virus infected pneumocytes and infectious virus in the lungs. These findings provide insights into the interplay between HIF signaling and RSV replication, and suggests new preventative and therapeutic strategies, including combinatorial therapies, for RSV infections and other respiratory pathogens.