HIF1α-mediated RelB/APOBEC3B downregulation allows Hepatitis B Virus persistence.
Riedl T., Faure-Dupuy S., Rolland M., Schuehle S., Hizir Z., Calderazzo S., Zhuang X., Wettengel J., Lopez MA., Barnault R., Mirakaj V., Prokosch S., Heide D., Leuchtenbergeg C., Schneider M., Heßling B., Stottmeier B., Wessbecher IM., Schirmacher P., McKeating JA., Protzer U., Durantel D., Lucifora J., Dejardin E., Heikenwalder M.
New therapeutic strategies against Hepatitis B virus (HBV) focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia inducible factor 1 alpha (HIF1α) stabilisation has been associated with impaired immune responses. HBV pathogenesis triggers chronic hepatitis-related scaring, leading inter alia to modulation of liver oxygenation and transient immune activation, both factors playing a role in HIF1α stabilisation. We addressed whether HIF1α interferes with immune-mediated induction of the cytidine deaminase APOBEC3B and subsequent covalently closed circular DNA (cccDNA) decay. Liver biopsies of chronic HBV patients (CHB) were analysed by IHC, and in situ hybridization. The effect of HIF1α induction/stabilisation on differentiated HepaRG or mice +/- HBV +/- LTβR-agonist (BS1) was assessed in vitro and in vivo. Induction of A3B and subsequent effects were analysed by RT-qPCR, immunoblotting, ChIP, ICC, and mass-spectrometry. Analysing CHB highlighted that areas with high HIF1α levels and low A3B expression correlated with high HBcAg, potentially representing a reservoir for HBV survival in immune-active patients. In vitro, HIF1α stabilisation, strongly impaired A3B expression and anti-HBV effect. Interestingly, HIF1α knock-down was sufficient to rescue the inhibition of A3B-upregulation and -mediated antiviral effects, whereas HIF2α knock-down had no effect. HIF1α stabilisation decreased the level of RelB protein but not its mRNA, which was confirmed in vivo. Noteworthy, this function of HIF1α was independent of its partner ARNT. In conclusion, inhibiting HIF1α expression or stabilisation represents a novel anti-HBV strategy in the context of immune-mediated A3B induction. High HIF1α, mediated by hypoxia or inflammation, offers a reservoir for HBV survival in vivo, and should be considered as a restricting factor in the development of novel immune therapies.