Herpes Simplex Virus disrupts the HIF transcription network to block a potent innate antiviral program
During virus infections, nucleic acids are sensed by pattern recognition receptors of the innate immune system to induce the type I (IFN) response. In addition, virus infections alter multiple cellular processes, which may also induce host defense. We performed transcriptome analysis of disrupted cellular transcripts in herpes simplex virus (HSV)-infected cells, and found that HSV infection down-regulates the hypoxia-inducible factor (HIF) transcription network in permissive cells of neuronal and epithelial origin. Importantly, HIF1A activation induced antiviral activity against HSV in neuronal cell lines and human stem cell-derived neurons, and blocked replication of a panel of neurotropic viruses. At the mechanistic level, HIF1A exerts antiviral activity through induction of autophagy and IFN regulatory factor 1-dependent expression of antiviral genes. Finally, mice with neuron-specific deficiency of HIF1A/2A exhibited elevated viral load and inflammatory responses in the CNS after HSV2 infection. Collectively, HIF1A senses a virus-induced stress signal to induce cell-intrinsic antiviral responses and limit inflammation.