Neuronal Hyperexcitability is a DLK-dependent Trigger of HSV-1 Reactivation that can be Induced by IL-1

Herpes Simplex Virus (HSV) establishes a latent infection in neurons and periodically reactivates to cause recurrent disease. The stimuli that act on neurons to trigger HSV reactivation have not been fully elucidated. Here we demonstrate that HSV reactivation is triggered by stimuli that induce neuronal hyperexcitability. Neuronal stimulation-induced reactivation was dependent on voltage-gated ion and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, demonstrating that neuronal activity is required for HSV reactivation. Hyperexcitability-induced reactivation was dependent on the neuronal specific pathway of DLK/JNK activation and progressed via an initial wave of viral gene expression that was independent of histone demethylase activity and linked to increased levels of histone phosphorylation. IL-1 induces neuronal hyperexcitability and is released under conditions of psychological stress and fever; both known triggers of clinical HSV reactivation. IL-1β treatment of sympathetic neurons induced histone phosphorylation, and importantly HSV reactivation, which was dependent on both DLK and neuronal excitability. Thus, HSV co-opts an innate immune pathway resulting from IL-1 stimulation of sympathetic neurons to induce reactivation from latency.