Activation of the hypoxia-inducible factor 1 alpha is necessary for type 1 interferon and IFN stimulatory gene expression during gammaherpesvirus infection

Abstract

Abstract Oxygen availability and the hypoxia-inducible factor 1 pathway (HIF1) influence the activity of cells involved in immune responses. Initially described as a master regulator of cellular adaptation to low oxygen concentration, activation of the hypoxia-inducible factor 1 alpha (HIF1α) is now recognized as an integral part of inflammatory cytokines production, phagocytic activity and bacterial killing by myeloid-derived cells. The goal of our studies is to determine the role of HIF1α during antiviral responses. We measure type 1 interferon gene expression in mouse embryonic fibroblasts lacking HIF1α activity (HIF1α Null MEFs) during early infection against the DNA virus, murine gammaherpesvirus 68 (MHV68). We recently reported that MHV68 activates HIF1atranscription activity and this is necessary for viral replication. In this study, analysis of mRNA levels by real-time qPCR, revealed that IFNβ1 decreased by 5-fold in HIF1α Null MEFs following 8 hours post infection (hpi), relative to wild-type, whereas levels of IFNα4, IFNα6 remained unchanged. Consistently, transcript levels of the IFN-stimulated gene OAS1β were reduced 7-fold relative to HIF1α WT MEFs. However, at 24hpi absence of HIF1α diminished expression of IFNα4, IFNα6, IFNβ1, OAS1β, IFIT18 and ISG20. In conclusion, these results suggest that HIF1α activity plays an important role during antiviral responses against dsDNA viruses.