Human stem cell derived sensory neurons are positioned to support varicella zoster virus latency

Abstract

The neuropathogenesis of varicella-zoster virus (VZV) has been challenging to study due to the strict human tropism of the virus and the resultant difficulties in establishing tractable experimental models. In vivo, sensory neurons of the dorsal root ganglia and trigeminal ganglia serve as cellular niches that support viral latency, and VZV can subsequently reactivate from these cells to cause disease. Whether sensory neurons possess intrinsic properties that position them to serve as a reservoir of viral latency remains unknown. Here, we utilize a robust human sensory neuron system to investigate lytic infection and viral latency. We find that sensory neurons exhibit resistance to lytic infection by VZV. On the other hand, latent infection in sensory neurons is associated with an episomal-like configuration of viral DNA and expression of the VZV latency-associated transcript (VLT), thus closely mirroring the in vivo state. Moreover, despite the relative restriction in lytic infection, we demonstrate that viral reactivation is possible from latently infected sensory neurons. Taken together, our data suggest that human sensory neurons possess intrinsic properties that serve to facilitate their role as a latent reservoir of VZV. IMPORTANCEVaricella-zoster virus (VZV) has infected over 90% of people worldwide. Following primary infection, the virus can remain dormant in the nervous system and may reactivate later in life, with potentially severe consequences. Here, we develop a model of VZV infection in human sensory neurons in order to determine whether these cells are intrinsically positioned to support latency and reactivation. We find that human sensory neurons are relatively resistant to lytic infection, but can support latency and reactivation. Moreover, during in vitro latency human sensory neurons, but not other neurons, express the newly discovered VZV latency-associated transcript (VLT), thus closely mirroring the in vivo latent state. Taken together, these data indicate that human sensory neurons are uniquely positioned to support latency. We anticipate that this human sensory neuron model will serve to facilitate further understanding of the mechanisms of VZV latency and reactivation.