The attenuated genotype of varicella-zoster virus includes an ORF0 transitional stop codon mutation

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

doi:10.1128/JVI.01067-12

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The attenuated genotype of varicella-zoster virus includes an ORF0 transitional stop codon mutation

Journal article

Open access

Peer reviewed

The attenuated genotype of varicella-zoster virus includes an ORF0 transitional stop codon mutation

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

Journal of virology, Vol.86(19), pp.10695-10703

10/2012

DOI: 10.1128/JVI.01067-12

PMCID: PMC3457260

PMID: 22837206

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Abstract

Varicella-zoster virus (VZV) is the first of the human herpesviruses to be attenuated and subsequently approved as a live vaccine to prevent varicella and herpes zoster. Both the attenuated VZV vaccine, called vaccine Oka or vOka, and the parental strain pOka have been completely sequenced. Yet the specific determinants of attenuation are uncertain. The open reading frame (ORF) with the most single nucleotide polymorphisms (SNPs), ORF62, encodes the regulatory protein IE62, but IE62 studies have failed to define a specific SNP associated with attenuation. We have completed next-generation sequencing of the VZV Ellen genome, a strain known to be highly attenuated by its very limited replication in human skin xenografts in the SCID mouse model of VZV pathogenesis. A comparative analysis of the Ellen sequence with all other complete VZV sequences was extremely informative. In particular, an unexpected finding was a stop codon mutation in Ellen ORF0 (herpes simplex virus UL56 homolog) identical to one found in vOka, combined with the absence of polymorphisms in most Ellen ORFs that were known to be mutated in vOka. The mutated ORF0 protein was also imaged in both two dimensions and three dimensions by confocal microscopy. The probability of two VZV strains not connected by a recent common ancestor having an identical ORF0 SNP by chance would be 1 × 10(-8), in other words, extremely unlikely. Taken together, these bioinformatics analyses strongly suggest that the stop codon ORF0 SNP is one of the determinants of the attenuation genotype of live VZV vaccines.

Genome, Viral

Computational Biology - methods

Immunoprecipitation

Humans

Open Reading Frames

Molecular Sequence Data

Genotype

Mice, SCID

Microscopy, Confocal - methods

Sequence Analysis, DNA

Herpesvirus 3, Human - genetics

Polymorphism, Genetic

Immediate-Early Proteins - metabolism

Animals

Viral Envelope Proteins - metabolism

Trans-Activators - metabolism

Mice

Polymorphism, Single Nucleotide

Mutation

Codon, Terminator

Fibroblasts - metabolism

Vaccines, Attenuated - genetics

Details

Title: Subtitle: The attenuated genotype of varicella-zoster virus includes an ORF0 transitional stop codon mutation
Creators: Geoffrey A Peters - National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
Shaun D Tyler
John E Carpenter
Wallen Jackson
Yasuko Mori
Ann M Arvin
Charles Grose
Resource Type: Journal article
Publication Details: Journal of virology, Vol.86(19), pp.10695-10703
DOI: 10.1128/JVI.01067-12
PMID: 22837206
PMCID: PMC3457260
ISSN: 0022-538X
eISSN: 1098-5514
Grant note: R01 AI053846 / NIAID NIH HHS R01 AI089716 / NIAID NIH HHS AI89716 / NIAID NIH HHS AI53846 / NIAID NIH HHS
Language: English
Date published: 10/2012
Academic Unit: Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984093347602771

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