Aberrant infection and persistence of varicella-zoster virus in human dorsal root ganglia in vivo in the absence of glycoprotein I.
Varicella-zoster virus (VZV) causes varicella, establishes latency in sensory ganglia, and reactivates as herpes zoster. Human dorsal root ganglia (DRGs) xenografts in immunodeficient mice provide a model for evaluating VZV neuropathogenesis. Our investigation of the role of glycoprotein I (gI), which is dispensable in vitro, examines the functions of a VZV gene product during infection of human neural cells in vivo. Whereas intact recombinant Oka (rOka) initiated a short replicative phase followed by persistence in DRGs, the gI deletion mutant, rOkaDeltagI, showed prolonged replication with no transition to persistence up to 70 days after infection. Only a few varicella-zoster nucleocapsids and cytoplasmic virions were observed in neurons, and the major VZV glycoprotein, gE, was retained in the rough endoplasmic reticulum in the absence of gI. VZV neurotropism was not disrupted when DRG xenografts were infected with rOka mutants lacking gI promoter elements that bind cellular transactivators, specificity factor 1 (Sp1) and upstream stimulatory factor (USF). Because gI is essential and Sp1 and USF contribute to VZV pathogenesis in skin and T cells in vivo, these DRG experiments indicate that the genetic requirements for VZV infection are less stringent in neural cells in vivo. The observations demonstrate that gI is important for VZV neurotropism and suggest that a strategy to reduce neurovirulence by deleting gI could prolong active infection in human DRGs.
Zerboni
Leigh
L
Departments of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA. zerboni@stanford.edu
Reichelt
Mike
M
Jones
Carol D
CD
Zehnder
James L
JL
Ito
Hideki
H
Arvin
Ann M
AM
D000818:Animals; D002644:Chickenpox / Q000276:immunology* / Q000473:pathology; D004279:DNA, Viral / Q000235:genetics; D005727:Ganglia, Spinal / Q000473:pathology / Q000637:transplantation / Q000821:virology*; D017353:Gene Deletion; D016679:Genome, Viral; D014645:Herpesvirus 3, Human / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D016366:Open Reading Frames; D011401:Promoter Regions, Genetic; D011995:Recombination, Genetic; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D014759:Viral Envelope Proteins / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics
D004279:DNA, Viral; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C056913:glycoprotein E, varicella-zoster virus
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