The Attenuated Genotype of Varicella-Zoster Virus Includes an ORF0 Transitional Stop Codon Mutation

Peters, Geoffrey A.; Tyler, Shaun; Carpenter, John E.; Jackson, Wallen; Mori, Yasuko; Arvin, Ann M.; Grose, Charles

doi:10.1128/jvi.01067-12

Cited by 44 publications

(33 citation statements)

References 37 publications

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“…Five VZV ORFs (ORF1, ORF2, ORF13, ORF32, ORF57) have no known HSV homolog (10, 46), while 9 HSV ORFs (γ34.5, UL45, US2, US4, US5, US6, US8.5, US11, US12) have no known VZV homolog. Amongst these 9 (mid-lower portion of Fig.…”

Section: Resultsmentioning

confidence: 99%

Extensive CD4 and CD8 T Cell Cross-Reactivity between Alphaherpesviruses

Jing

Laing

Dong

et al. 2016

The Journal of Immunology

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The alphaherpesvirinae subfamily includes HSV types 1 and 2 and the sequence-divergent pathogen varicella zoster virus (VZV). T cells, controlled by TCR and HLA molecules that tolerate limited epitope amino acid variation, might cross-react between these microbes. We show that memory PBMC expansion with either HSV or VZV enriches for CD4 T cell lines that recognize the other agent at the whole virus, protein, and peptide levels, consistent with bi-directional cross-reactivity. HSV-specific CD4 T cells recovered from HSV seronegative persons can be partially explained by such VZV cross-reactivity. HSV-1-reactive CD8 T cells also cross-react with VZV-infected cells, full-length VZV proteins, and VZV peptides, and kill VZV-infected dermal fibroblasts. Mono- and cross-reactive CD8 T cells use distinct TCRB CDR3 sequences. Cross-reactivity to VZV is reconstituted by cloning and expressing TCRA/TCRB receptors from T-cells that are initially isolated using HSV reagents. Overall, we define 13 novel CD4 and CD8 HSV-VZV cross-reactive epitopes and strongly imply additional cross-reactive peptide sets. Viral proteins can harbor both CD4 and CD8 HSV/VZV cross-reactive epitopes. Quantitative estimates of HSV/VZV cross-reactivity for both CD4 and CD8 T cells vary from 10-50%. Based on these findings, we hypothesize host herpesvirus immune history may influence the pathogenesis and clinical outcome of subsequent infections or vaccinations for related pathogens, and that cross-reactive epitopes and TCRs may be useful for multi-alphaherpesvirus vaccine design and adoptive cellular therapy.

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Section: Resultsmentioning

confidence: 99%

Extensive CD4 and CD8 T Cell Cross-Reactivity between Alphaherpesviruses

Jing

Laing

Dong

et al. 2016

The Journal of Immunology

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“…Live, attenuated vOka consists of a mixture of distinct VZV genotypes, with 42 single nucleotide polymorphisms distinguishing vOka from the wild-type Oka parent strain 120,121 . The exact mechanisms for the attenuation of VZV in live vaccines remain unknown; mutations in ORF62 were identified in vOka 122 and mutations at positions 106262, 107252 and 108111 in ORF62 are important 112 , as is a stop codon mutation at position 560 in ORF0 (REF 123). These mutations, particularly the unique mutations at positions 106262 and 108111 in ORF62 , can be used to differentiate parental Oka and other wild-type strains of VZV from vOka 104,112 .…”

Section: Diagnosis Screening and Preventionmentioning

confidence: 99%

Varicella zoster virus infection

Gershon

Breuer

Cohen

et al. 2015

Nat Rev Dis Primers

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Infection with varicella zoster virus (VZV) causes varicella (chickenpox), which can be severe in immunocompromised individuals, infants and adults. Primary infection is followed by latency in ganglionic neurons. During this period, no virus particles are produced and no obvious neuronal damage occurs. Reactivation of the virus leads to virus replication, which causes zoster (shingles) in tissues innervated by the involved neurons, inflammation and cell death — a process that can lead to persistent radicular pain (postherpetic neuralgia). The pathogenesis of postherpetic neuralgia is unknown and it is difficult to treat. Furthermore, other zoster complications can develop, including myelitis, cranial nerve palsies, meningitis, stroke (vasculopathy), retinitis, and gastroenterological infections such as ulcers, pancreatitis and hepatitis. VZV is the only human herpesvirus for which highly effective vaccines are available. After varicella or vaccination, both wild-type and vaccine-type VZV establish latency, and long-term immunity to varicella develops. However, immunity does not protect against reactivation. Thus, two vaccines are used: one to prevent varicella and one to prevent zoster. In this Primer we discuss the pathogenesis, diagnosis, treatment, and prevention of VZV infections, with an emphasis on the molecular events that regulate these diseases. For an illustrated summary of this Primer, visit: http://go.nature.com/14×VI1

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“…Images of the labeled infected cells were collected on a laser-scanning confocal microscope as described previously (8). A three-dimensional (3D) image of a single infected cell was generated from a z-stack using Imaris software as described previously (9). At 14 d.p.i., neurons in 6-well cell culture plates were fixed in 2.5% glutaraldeyde for 30 min at room temperature, further fixed with 1% OsO 4 -2.5% potassium ferrocyanide for 1 h, washed three times in deionized water, and stained with 4% uranyl acetate for 1 h as described previously (10).…”

Section: Neuronal Cells and Vzv Infection Icell Neurons (Cellular Dymentioning

confidence: 99%

Aberrant Virion Assembly and Limited Glycoprotein C Production in Varicella-Zoster Virus-Infected Neurons

Grose

Cohrs

et al. 2013

J Virol

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Highly pure (>95%) terminally differentiated neurons derived from pluripotent stem cells appear healthy at 2 weeks after infection with varicella-zoster virus (VZV), and the cell culture medium contains no infectious virus. Analysis of the healthy-appearing neurons revealed VZV DNA, transcripts, and proteins corresponding to the VZV immediate early, early, and late kinetic phases of replication. Herein, we further characterized virus in these neuronal cells, focusing on (i) transcription and expression of late VZV glycoprotein C (gC) open reading frame 14 (ORF14) and (ii) ultrastructural features of virus particles in neurons. The analysis showed that gC was not expressed in most infected neurons and gC expression was markedly reduced in a minority of VZV-infected neurons. In contrast, expression of the early-late VZV gE glycoprotein (ORF68) was abundant. Transcript analysis also showed decreased gC transcription compared with gE. Examination of viral structure by high-resolution transmission electron microscopy revealed fewer viral particles than typically observed in cells productively infected with VZV. Furthermore, viral particles were more aberrant, in that most capsids in the nuclei lacked a dense core and most enveloped particles in the cytoplasm were light particles (envelopes without capsids). Together, these results suggest a considerable deficiency in late-phase replication and viral assembly during VZV infection of neurons in culture.V aricella-zoster virus (VZV) is an exclusively human neurotropic alphaherpesvirus. Primary infection usually produces varicella (chickenpox), after which virus becomes latent in ganglionic neurons along the entire neuraxis, revealing a unique nonlytic relationship of VZV with neurons, in contrast to productive infection of cells derived from other organs (1). Initial attempts to explore the VZV-neuron relationship were done with human ganglionic cells cultured in vitro and experimentally infected with VZV. While both neurons and nonneuronal cells became infected, productive infection of nonneuronal cells resulted in destruction of the entire culture (2, 3). Later studies in which VZV-infected human fetal fibroblasts were cocultivated with explanted human fetal dorsal root ganglia indicated that neurons were resistant to apoptosis (4). Recently, heterogeneous cultures derived from human embryonic stem cells that contained neurons were infected with VZV, but again productive infection ensued, presumably due to the presence of a significant proportion of nonneuronal cells (5). When differentiated human neural stem cells that were Ͼ90% neurons based on immunostaining were infected with VZV, no cytopathic effect developed, and VZV DNA, virus-specific transcripts, and proteins were detected in healthy-appearing neurons (6). Similarly, weeks after VZV infection of cultures containing Ͼ95% terminally differentiated human neurons derived from pluripotent stem cells, the neurons appeared healthy, and the tissue culture medium did not contain infectious virus (7); none of the cell...

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The Attenuated Genotype of Varicella-Zoster Virus Includes an ORF0 Transitional Stop Codon Mutation

Cited by 44 publications

References 37 publications

Extensive CD4 and CD8 T Cell Cross-Reactivity between Alphaherpesviruses

Extensive CD4 and CD8 T Cell Cross-Reactivity between Alphaherpesviruses

Varicella zoster virus infection

Aberrant Virion Assembly and Limited Glycoprotein C Production in Varicella-Zoster Virus-Infected Neurons

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