Defining the role of hypoxia inducible factors in viral replication and pathogenesis (360G-Wellcome-200838_Z_16_Z)

£1,507,759

Viruses are obligate parasites that have evolved to manipulate their host to their advantage. Hypoxia inducible factors (HIFs) are regulated by oxygen-dependent and independent stress signals and control genes involved in energy metabolism, inflammation and angiogenesis. HIF-signalling pathways are perturbed in many diseases including cancer and inflammatory conditions, however, their role in viral infection is poorly understood. My group’s recent discovery that HIF-1alpha regulates HBV and HCV infection highlights an unexpected role for these transcription factors in the replicative lifecycle of these liver-tropic DNA and RNA oncogenic viruses. We have shown that HBV and HCV activate HIF and associated-transcriptional activity, suggesting a role in viral-associated cancer. We will use state-of-art HBV and HCV replication model systems, inducible-HIF hepatocellular knock-out mice, HBV transgenic mice and samples from human HCC to dissect the role of HIFs in virus replication and pathogenesis. Of note, several other oncogenic viruses (EBV, KSHV, HPV) also stabilize HIF, highlighting a convergence of diverse viruses targeting this pathway. Since viruses replicate in tissues with variable oxygen tensions in vivo, understanding the role HIFs play in viral replication will inform the design of physiologically relevant systems to model virus-host interactions.

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Grant Details

Amount Awarded 1507759
Applicant Surname McKeating
Approval Committee Science Interview Panel
Award Date 2016-04-05T00:00:00+00:00
Financial Year 2015/16
Grant Programme: Title Investigator Award in Science
Internal ID 200838/Z/16/Z
Lead Applicant Prof Jane McKeating
Partnership Value 1507759
Planned Dates: End Date 2023-09-01T00:00:00+00:00
Planned Dates: Start Date 2017-08-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East