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Neuron-virus interactions that occur during herpes simplex virus (HSV) infection are not fully understood. Neurons are the site of lifelong latency and are a crucial target for long-term suppressive therapy or viral clearance. A reproducible neuronal model of human origin would facilitate studies of HSV and other neurotropic viruses. Current neuronal models in the herpesvirus field vary widely and have caveats including incomplete differentiation, non-human origins, or the use of dividing cells that have neuropotential, but lack neuronal morphology. Here we use a robust approach to differentiate human SH-SY5Y neuroblastoma cells over 2.5 weeks, producing a uniform population of mature human neuronal cells. We demonstrate that terminally differentiated SH-SY5Y cells have neuronal morphology and express proteins with subcellular localization indicative of mature neurons. These neuronal cells are able to support a productive HSV-1 infection, with kinetics and overall titer similar to those seen in undifferentiated SH-SY5Y cells and the related SK-N-SH cell line. However terminally differentiated, neuronal SH-SY5Y cells release significantly less extracellular HSV-1 by 24 hpi, suggesting a unique neuronal response to viral infection. With this model, we are able to distinguish differences in neuronal spread between two strains of HSV-1. We also show expression of the antiviral protein cGAS in neuronal SH-SY5Y cells, which is the first demonstration of the presence of this protein in non-epithelial cells. These data provide a model for studying neuron-virus interactions at the single-cell level as well as via bulk biochemistry, and will be advantageous for the study of neurotropic viruses in vitroImportance Herpes simplex virus (HSV) affects millions of people worldwide, causing painful oral and genital lesions, in addition to a multitude of more severe symptoms such as eye disease, neonatal infection, and in rare cases, encephalitis. Presently, there is no cure available to treat those infected or prevent future transmission. Due to the ability of this virus to cause a persistent, lifelong infection in the peripheral nervous system, the virus remains within the host for life. To better understand the basis of virus-neuron interactions that allow this virus to persist within the host peripheral nervous system, improved neuronal models are required. This research details a cost-effective and scalable human neuronal model system that can be used to study many neurotropic viruses such as HSV, Zika virus, dengue virus, and rabies virus.

Differentiated Human SH-SY5Y Cells Provide a Reductionist Model of Herpes Simplex Virus 1 Neurotropism