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Activation of hypoxia inducible factors (HIFs) by either hypoxia or drug treatment inhibits SARS-CoV-2 entry and replication in lung epithelial cells, raising the potential of using clinically licensed HIF activators to prevent and/or treat COVID-19.

Hypoxia inducible factor (HIF) is a protein that is central to the body’s response to low oxygen (hypoxia). Under conditions of high oxygen, HIF is modified with hydroxyl chemical groups by the oxygen-sensing prolyl hydroxylase domain (PHD) enzymes, which target HIF for degradation. When oxygen levels are low, HIF is no longer hydroxylated by PHD enzymes and activates the transcription of genes involved in responding to low oxygen, including genes regulating red blood cell production, cell metabolism, proliferation and immune regulation.

COVID-19 disease, caused by the novel coronavirus SARS-CoV-2, is characterised by low oxygen levels throughout the body. While previous studies have shown that hypoxia affects the replication of several viruses including Influenza A and human immunodeficiency virus, it is not yet known whether hypoxia impacts SARS-CoV-2 infection. Understanding the interplay between hypoxia and SARS-CoV-2 infection would shed light on possible COVID-19 prevention or treatment strategies.

Dr Peter Wing, Dr Tom Keeley and colleagues from the laboratories of Professor Jane McKeating (Nuffield Department of Medicine), Dr Tammie Bishop and Professor Sir Peter Ratcliffe (Ludwig Oxford and Nuffield Department of Medicine) demonstrate that activation of HIF, either by hypoxia or by pharmacological inhibition of the PHD enzymes, reduces levels of the receptor that is required for SARS-CoV-2 entry into host cells (angiotensin-converting enzyme (ACE2)) and markedly decreases the entry of SARS-CoV-2 into lung epithelial cells.

Their research, which is published in the journal Cell Reports, further uncovers that hypoxia and PHD inhibition reduce SARS-CoV-2 replication in infected lung epithelial cells, including the recently emerged UK and South African variants. Together, this research shows that pharmacological activation of HIF inhibits several stages of the SARS-CoV-2 life cycle, including viral entry and genome replication.

The findings of this study are promising, since PHD inhibitors including Roxadustat, are clinically approved for the treatment of patients with chronic kidney disease. However, because the effects of HIF on the body are complex, further investigation using animal studies and/or clinical trials is needed to assess whether PHD inhibitors would have a net benefit in preventing and/or treating COVID-19.

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