Modeling Varicella Zoster Virus Persistence and Reactivation - Closer to Resolving a Perplexing Persistent State

Abstract

The latent state of the human herpesvirus varicella zoster virus (VZV) has remained enigmatic and controversial. While it is well substantiated that VZV persistence is established in neurons after the primary infection (varicella or chickenpox), we know little of the types of neurons harboring latent virus genomes, if all can potentially reactivate, what exactly drives the reactivation process, and the role of immunity in the control of latency. Viral gene expression during latency has been particularly difficult to resolve, although very recent advances indicate that it is more restrictive than was once thought. We do not yet understand how genes expressed in latency function in the maintenance and reactivation processes. Model systems of latency are needed to pursue these questions. This has been especially challenging for VZV because the development of in vivo models of VZV infection has proven difficult. Given that up to one third of the population will clinically reactivate VZV to develop herpes zoster (shingles) and suffer from its common long term problematic sequelae, there is still a need for both in vivo and in vitro model systems. This review will summarize the evolution of models of VZV persistence and address insights that have arisen from the establishment of new in vitro human neuron culture systems that not only harbor a latent state, but permit experimental reactivation and renewed virus production. These models will be discussed in light of the recent data gleaned from the study of VZV latency in human cadaver ganglia.

Keywords: animal models; human neuron culture models; latency; reactivation; varicella zoster virus.

FIGURE 1

Latent VZV infections established in hESC-neurons in microfluidic devices can be experimentally reactivated. hESC-neurons are infected axonally in microfluidic devices that separate neuronal soma from axons. (A–C) Depicts a microfluidic chamber that separates neuronal soma (CB) from axons (Ax). VZV infection is established in the axonal compartment, allowing VZV to be transported through axons into some somata, in which a quiescent infection is established. Upon stimulation with PI3K inhibitor LY294002 and incubation of cultures at 34°C, virus in some latently infected neurons is reactivated and productive infection is re-established. Ch = microfluidic channels that connect the soma and axon compartments. (D) A diagrammatic representation shows the process of axonal infection of neurons with VZV, establishment of latency, and reactivation.