Varicella-zoster virus infection of human dorsal root ganglia in vivo.
Varicella-zoster virus (VZV) causes varicella and establishes latency in sensory ganglia. VZV reactivation results in herpes zoster. We developed a model using human dorsal root ganglion (DRG) xenografts in severe combined immunodeficient (SCID) mice to investigate VZV infection of differentiated neurons and satellite cells in vivo. DRG engrafted under the kidney capsule and contained neurons and satellite cells within a typical DRG architecture. VZV clinical isolates infected the neurons within DRG. At 14 days postinfection, VZ virions were detected by electron microscopy in neuronal cell nuclei and cytoplasm but not in satellite cells. The VZV genome copy number was 7.1 x 10(7) to 8.0 x 10(8) copies per 10(5) cells, and infectious virus was recovered. This initial phase of viral replication was followed within 4-8 weeks by a transition to VZV latency, characterized by the absence of infectious virus release, the cessation of virion assembly, and a reduction in VZV genome copies to 3.7 x 10(5) to 4.7 x 10(6) per 10(5) cells. VZV persistence in DRG was achieved without any requirement for VZV-specific adaptive immunity and was associated with continued transcription of the ORF63 regulatory gene. The live attenuated varicella vaccine virus exhibited the same pattern of short-term replication, persistence of viral DNA, and prominent ORF63 transcription as the clinical isolates. VZV-infected T cells transferred virus from the circulation into DRG, suggesting that VZV lymphotropism facilitates its neurotropism. DRG xenografts may be useful for investigating neuropathogenic mechanisms of other human viruses.
Zerboni
Leigh
L
Department of Pediatrics,Stanford University School of Medicine, Stanford, CA 94305, USA. zerboni@stanford.edu
Ku
Chia-Chi
CC
Jones
Carol D
CD
Zehnder
James L
JL
Arvin
Ann M
AM
D000818:Animals; D002644:Chickenpox / Q000473:pathology*; D017931:DNA Primers; D005727:Ganglia, Spinal / Q000473:pathology / Q000637:transplantation / Q000821:virology*; D016679:Genome, Viral; D014645:Herpesvirus 3, Human / Q000235:genetics* / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D016513:Mice, SCID; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000648:ultrastructure / Q000821:virology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027161:Satellite Cells, Perineuronal / Q000648:ultrastructure / Q000821:virology; D013601:T-Lymphocytes / Q000821:virology; D014183:Transplantation, Heterologous; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism; D014771:Virion / Q000502:physiology / Q000648:ultrastructure; D014779:Virus Replication / Q000502:physiology
D017931:DNA Primers; D017874:Immediate-Early Proteins; D014759:Viral Envelope Proteins; C074551:immediate early protein 63, Human herpesvirus 3