A Neuron-Specific Host MicroRNA Targets Herpes Simplex Virus-1 ICP0 Expression and Promotes Latency

After infecting peripheral sites, herpes simplex virus (HSV) invades the nervous system and initiates latent infection in sensory neurons. Establishment and maintenance of HSV latency require host survival, and entail repression of productive cycle (“lytic”) viral gene expression. We find that a neuron-specific microRNA, miR-138, represses expression of ICP0, a viral transactivator of lytic gene expression. A mutant HSV-1 (M138) with disrupted miR-138 target sites in ICP0 mRNA exhibits enhanced expression of ICP0 and other lytic proteins in infected neuronal cells in culture. Following corneal inoculation, M138-infected mice have higher levels of ICP0 and lytic transcripts in trigeminal ganglia during establishment of latency, and exhibit increased mortality and encephalitis symptoms. After full establishment of latency, the fraction of trigeminal ganglia harboring detectable lytic transcripts is greater in M138-infected mice. Thus, miR-138 is a neuronal factor that represses HSV-1 lytic gene expression, promoting host survival and viral latency. [Display omitted] •miR-138 is a neuron-specific microRNA•miR-138 represses expression of the HSV-1 lytic gene transactivator, ICP0•Mutating miR-138 target sites in ICP0 causes higher lytic gene expression in neurons•Mutating these miR-138 sites results in increased host morbidity and mortality Herpes simplex virus forms latent infections in neurons, but how neurons contribute to latency has remained largely undefined. Pan et al. identify a neuron-specific microRNA, miR-138, that reduces the expression of a viral gene activator and “lytic” viral gene expression, and promotes host survival and viral latency.