Role of Hypoxia-Inducible Factors (HIFs) in Respiratory Syncytial Virus Infection

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PROJECT SUMMARY/ABSTRACT Several viruses have been shown to induce metabolic reprogramming of host cells to establish productive infections. One common mechanism utilized by viruses is the stabilization of hypoxia-inducible-factors (HIF). The HIF complex, comprised of an inducible α subunit (HIF-1α or HIF-2α) and a constitutively expressed β subunit (HIF-1β), is known to control diverse transcriptional processes in response to hypoxia and other disease states. The use of both HIF inhibitors and stabilizers has been investigated in models of cancer, autoimmunity, and non-infectious acute lung injury, with several compounds for both classes currently being tested in phase 3 clinical trials for a variety of clinical disorders. However, there are no publications describing the use of a HIF specific inhibitors or stabilizers in in vivo models of viral infections. In vitro studies have suggested that inhibiting HIF-1α could represent an effective anti-viral strategy, including against respiratory viruses such as respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, our preliminary data in a mouse model of RSV infection, the leading cause of severe acute lung illness in infants for which there are no effective therapeutics or licensed vaccines, did not support this strategy, as we found that inhibition of HIF-1α worsen clinical disease and favors viral replication, while stabilization of HIF proteins improves clinical disease and lung function. The central hypothesis of this application is that during RSV infection (and possibly other respiratory viruses) HIFs mediate activation and survival of key immune cells that control antiviral responses while maintaining lung integrity and function. We will test this hypothesis in a well-established mouse model of RSV infection. In Specific Aim 1, we will determine the contributions of HIF-1α and/or HIF-2α to RSV-mediated clinical disease, lung function, immune modulation, and viral replication using inhibitors specific for each of the HIF-αsubunits. In Specific Aim 2, we will test the hypothesis that HIF stabilization protects the airways from experimental RSV infection and modulate antiviral immune responses, using similar disease and viral outcomes. This is a novel project with a long-term goal to uncover the unique and complex contribution of HIFs to both antiviral immunity and lung pathophysiology, and with wider relevance for human respiratory infections. This contribution is significant as these studies will provide important new information for ongoing clinical trials of HIF inhibitors, used in patients with cancers and other diseases who could be at higher risk for more severe respiratory viral infections, as well the potential use of HIF stabilizers as therapeutic approach for respiratory virus associated lung diseases.