Varicella-zoster virus infection of human neural cells in vivo

Abstract

Varicella-zoster virus (VZV) establishes latency in sensory ganglia and causes herpes zoster upon reactivation. These investigations in a nonobese diabetic severe combined immunodeficient mousehuman neural cell model showed that VZV infected both neurons and glial cells and spread efficiently from cell to cell in vivo. Neural cell morphology and protein synthesis were preserved, in contrast to destruction of epithelial cells by VZV. Expression of VZV genes in neural cells was characterized by nuclear retention of the major viral transactivating protein and a block in synthesis of the predominant envelope glycoprotein. The attenuated VZV vaccine strain retained infectivity for neurons and glial cells in vivo. VZV gene expression in differentiated human neural cells in vivo differs from neural infection by herpes simplex virus, which is characterized by latency-associated transcripts, and from lytic VZV replication in skin. The chimeric nonobese diabetic severe combined immunodeficient mouse model may be useful for investigating other neurotropic human viruses.

Varicella-Zoster Virus Infection of Differentiated Human Neural Stem Cells

“…There have been four other studies of VZV interaction with human neurons in vitro (2,13,14,21). All were different than ours in that neuronal infection was established by cocultivation rather than with cell-free virus, and only one of the studies analyzed neurons for VZV gene expression weeks after infection (21).…”

“…The second study by the same laboratory also infected explants of human fetal dorsal root ganglia and showed that productive virus infection peaked at day 4 but dropped dramatically by day 5 (13); infected neurons were not analyzed weeks later, which would have allowed a comparison of viral gene expression with our neuronal cultures. The third study used human neural stem cells isolated from fetal brain that were transplanted into nonobese diabetic SCID mouse brains, after which they were allowed to differentiate in vivo, followed by infection with VZV (2). In this chimeric model, VZV was found in both neurons and glial cells.…”

“…Because no satisfactory animal model exists to study the interaction of VZV with neurons, alternate models have been developed. For example, immunedeficient SCID mice have had human neural stem cells or human ganglia transplanted, followed by infection with VZV and examination of infected neurons (2,21). VZV has been also shown to infect cultured neurons from guinea pig enteric ganglia (8).…”

Varicella-Zoster Virus ORF63 Inhibits Apoptosis of Primary Human Neurons

“…Interestingly, in a model of VZV latent infection using cotton rats, ORF63 recently has been shown to play an important role in the efficient establishment of VZV latency in these animals, although the mechanism underlying this function remains to be defined (8,9). Several novel systems for investigating the neurotropism of VZV in vivo using chimeric NOD-SCID mouse-human neural cells or intact DRG xenografts also recently have been described (4,38). Studies using the chimeric NOD-SCID mouse-human neural cell model found that cells infected with the single-copy mutant of ORF63, rOka⌬ORF70, showed the same cellular localization as pOka and vOka, which have two copies of ORF63 (4).…”

Productive Varicella-Zoster Virus Infection of Cultured Intact Human Ganglia

“…Grafting of neural cells has been used to examine infection of neurons and glial cells (2). In a variation of this model, intact human fetal dorsal root ganglia (DRG) have been grafted into SCID-hu mice to show that after initial productive infection, VZV persisted in a form consistent with the establishment of latency (29).…”