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Abstract
Varicella zoster virus (VZV) is a highly prevalent human pathogen that causes varicella (chicken pox) during primary infection and establishes latency in peripheral neurons. Symptomatic reactivation often presents as zoster (shingles), but it has also been linked to life-threatening diseases such as encephalitis, vasculopathy and meningitis. Zoster may be followed by postherpetic neuralgia, neuropathic pain lasting after resolution of the rash. The mechanisms of varicella zoster virus (VZV) latency and reactivation are not well characterized. This is in part due to the human-specific nature of VZV that precludes the use of most animal and animal-derived neuronal models. Recently, in vitro models of VZV latency and reactivation using human neurons derived from stem cells have been established facilitating an understanding of the mechanisms leading to VZV latency and reactivation. From the models, c-Jun N-terminal kinase (JNK), phosphoinositide 3-kinase (PI3K) and nerve growth factor (NGF) have all been implicated as potential modulators of VZV latency/reactivation. Additionally, it was shown that the vaccine-strain of VZV is impaired for reactivation. These models may also aid in the generation of prophylactic and therapeutic strategies to treat VZV-associated pathologies. This review summarizes and analyzes the current human neuronal models used to study VZV latency and reactivation, and provides some strategies for their improvement.
Highlights
Varicella zoster virus (VZV) is a human neurotropic virus that establishes latency in sensory and autonomic neurons of the peripheral nervous system (PNS)
Since VZV establishes latency in both sympathetic and sensory neurons, a thorough characterization of the neurons employed in the VZV latency models would help determine whether neurotrophic factors other than nerve growth factor (NGF) are important for maintaining latency
In the last few years, the field of VZV latency and reactivation has greatly advanced due to both the derivation of human neurons to perform mechanistic studies in vitro and advanced molecular techniques which led to the identification of VZV latency-associated transcript” (VLT) in vivo
Summary
Varicella zoster virus (VZV) is a human neurotropic virus that establishes latency in sensory and autonomic neurons of the peripheral nervous system (PNS). We review the current literature on VZV latency and reactivation obtained with human neurons, focusing on the currently available in vitro neuronal models. The use of these models has already shed light on critical aspects of VZV latency and reactivation and provides an opportunity to address unresolved questions. These are exactly that—models—attempting to recreate a state that only truly exists in vivo, where an intact immune system, support cells (e.g., Schwann cells), and a 3D matrix exists. As is reviewed in the “Concluding remarks and outlook” section, these models are very informative, but inherently all current models fall short of what presumably occurs in vivo
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