Effect of adenovirus infection on hypoxia inducible factor 1 pathway

Low oxygen (hypoxia) and stabilisation of the Hypoxia-Inducible Factor 1 alpha (HIF-1α) have been reported to be either beneficial or detrimental to the efficacy of candidate oncolytic viruses such as reovirus, vesicular stomatitis virus or Newcastle disease virus. We have found that Enadenotucirev (an oncolytic group B adenovirus) has increased activity in hypoxia compared with normoxia. In order to understand how hypoxia benefits EnAd, we studied the HIF-1 pathway during virus infection. Here we have shown that EnAd infection leads to down-regulation of the HIF-1α protein in certain virus-permissive cell lines in hypoxia. We also report a similar effect after infection with wild type adenoviruses (Ad5 and Ad11). To determine the mechanisms underlying this downregulation, we measured the mRNA levels of HIF-1α and its target genes by reverse transcription quantitative PCR and found that all three viruses down-regulate HIF-1α transcripts in both normoxia and hypoxia. We also found that this down-regulation is independent of the proteasome complex. Our data has also shown that AD293 cells (which have Ad5 E1 gene) have lower basal levels of HIF-1α protein compared to other cell lines. Since several studies suggest that adenovirus E1A regulates many cellular genes, we speculate that adenovirus mediated down-regulation of HIF1α mRNA is achieved by E1A. Future work will look at the role of E1A in regulating the HIF-1 pathway.