Abstract
Herpes zoster, the result of varicella-zoster virus (VZV) reactivation, is frequently complicated by difficult-to-treat chronic pain states termed postherpetic neuralgia (PHN). While there are no animal models of VZV-induced pain following viral reactivation, subcutaneous VZV inoculation of the rat causes long-term nocifensive behaviors indicative of mechanical and thermal hypersensitivity. Previous studies using UV-inactivated VZV in the rat model suggest viral gene expression is required for the development of pain behaviors. However, it remains unclear if complete infection processes are needed for VZV to induce hypersensitivity in this host. To further assess how gene expression and replication contribute, we developed and characterized three replication-conditional VZV using a protein degron system to achieve drug-dependent stability of essential viral proteins. Each virus was then assessed for induction of hypersensitivity in rats under replication permissive and nonpermissive conditions. VZV with a degron fused to ORF9p, a late structural protein that is required for virion assembly, induced nocifensive behaviors under both replication permissive and nonpermissive conditions, indicating that complete VZV replication is dispensable for the induction of hypersensitivity. This conclusion was confirmed by showing that a genetic deletion recombinant VZV lacking DNA packaging protein ORF54p still induced prolonged hypersensitivities in the rat. In contrast, VZV with a degron fused to the essential IE4 or IE63 proteins, which are involved in early gene regulation of expression, induced nocifensive behaviors only under replication permissive conditions, indicating importance of early gene expression events for induction of hypersensitivity. These data establish that while early viral gene expression is required for the development of nocifensive behaviors in the rat, complete replication is dispensable. We postulate this model reflects events leading to clinical PHN, in which a population of ganglionic neurons become abortively infected with VZV during reactivation and survive, but host signaling becomes altered in order to transmit ongoing pain.
Highlights
The human neurotropic herpesvirus, varicella-zoster virus (VZV), causes varicella upon primary infection and herpes zoster following reactivation from a latent state that was established during primary infection [1]
Varicella-zoster virus (VZV)-inoculated rats develop persistent behaviors that indicate the development of prolonged hypersensitivity that may model postherpetic neuralgia (PHN) seen in the clinic
Our results reveal the production of essential VZV regulatory proteins is required to induce nocifensive behaviors, but that full productive virus replication is dispensable
Summary
The human neurotropic herpesvirus, varicella-zoster virus (VZV), causes varicella (chickenpox) upon primary infection and herpes zoster (shingles, HZ) following reactivation from a latent state that was established during primary infection [1]. HZ will occur in about one-third of unvaccinated individuals in their lifetime and remains a major public health concern, owing to an expanding aged demographic that are at risk of HZ disease and morbidities. Incidence and disease severity increase significantly with advancing age and/or immune impairment [2]. While incidence of both primary and reactivated disease can be greatly reduced by vaccination [3,4,5,6], most adults remain at risk for HZ because they harbor latent, wild-type VZV within sensory ganglia, and uptake of HZ vaccines in the US is far from optimal [7]. Research continues into improved treatment and prevention strategies for HZ
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