Analysis of varicella zoster virus attenuation by evaluation of chimeric parent Oka/vaccine Oka recombinant viruses in skin xenografts in the SCIDhu mouse model

Zerboni, Leigh; Hinchliffe, Stewart J.; Sommer, Marvin; Ito, Hideki; Besser, Jaya; Stamatis, Shaye; Cheng, Jason; DiStefano, Daniel J.; Kraiouchkine, Nikolai; Shaw, Alan; Arvin, Ann M.

doi:10.1016/j.virol.2004.10.047

Cited by 53 publications

(48 citation statements)

References 35 publications

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“…Thus, attenuation of V-Oka is not solely the result of mutational events clustered within IE 62 but may include reduced expression in VZV ORFs 65, 66, and 67 that together reduce assembly and spread of virus. Such a notion is supported by recent studies in which overlapping cosmid sets were used to generate recombinant VZV; chimeric VZV containing P-Oka-derived sequences covering ORFs 30 to 55 on a V-Oka background displayed wild-type infectivity in skin xenografts (34). Together, the data suggest that diminished vaccine virus virulence reflects a combination of mutations acting to reduce V-Oka replication.…”

Section: Discussionmentioning

confidence: 77%

Comparison of Virus Transcription during Lytic Infection of the Oka Parental and Vaccine Strains of Varicella-Zoster Virus

Cohrs¹,

Gilden

Gomi

et al. 2006

J Virol

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Varicella-zoster virus (VZV) is a ubiquitous human pathogen. Primary infection causes varicella (chicken pox), after which virus becomes latent in cranial nerve, dorsal root, and autonomic ganglia. Virus reactivation, primarily in elderly individuals whose cell-mediated immune response to VZV is reduced, produces zoster (shingles). The Oka vaccine strain of VZV was developed by limited propagation in human (11 passages) and guinea pig (6 passages) embryo fibroblasts (32). Vaccination with the Oka vaccine strain of VZV effectively reduces disease produced by primary infection by approximately 85% (31). In the decade before vaccine licensure, an annual average of 94 deaths associated with primary varicella was reported in the United States (23). After vaccination was approved, there were three varicella-related deaths in 1997 and nine in 2002. Recently, a multicenter, randomized, doubleblind, placebo-controlled trial showed that both the incidence of zoster and the burden of illness due to virus reactivation were reduced Ͼ50% by vaccination of adults over age 60 years (mean age, 69 years) (27). In light of the vaccine success, investigators have begun to determine the molecular basis of virus attenuation. Comparison of the Oka parental (P-Oka) and vaccine (V-Oka) DNA sequences has revealed 63 sites that differ between P-Oka and V-Oka, including 27 sites where the nucleotide sequence could not be unambiguously determined. Also, sequence polymorphism is present in different vaccine preparations (29). Thus, V-Oka is not a pure virus strain but consists of a mixture of closely related viruses.The VZV genome contains regions of inverted repeated DNA sequences; consequently, 3 open reading frame (ORF) pairs (ORF 62 and ORF 71, ORF 63 and ORF 70, and ORF 64 and ORF 69) are diploid. Thus, 37 of the 63 mutated sites between P-Oka and V-Oka genomic DNA are unique mutations located within 21 ORFs. Ten mutations are found within ORF 62, which encodes IE 62, the major immediate-early transactivator of VZV gene transcription. Previous transienttransfection-based studies suggested that IE 62 derived from V-Oka is a less potent transactivator of VZV genes than the P-Oka-derived IE 62 (7-9). Here, we used well-characterized PCR-based macroarrays (5) to compare the global virus gene transcriptional activity of both the parental and vaccine strains of VZV during lytic infection. Array data were confirmed at the RNA level by quantitative cDNA dot blot analysis and at the protein level by Western blot analysis. The ability of IE 62 derived from P-Oka and V-Oka to transactivate selected VZV gene promoters was also determined. MATERIALS AND METHODSVirus and cells. P-Oka and V-Oka were kind gifts from M. Takahashi. V-Oka was from a Japanese vaccine lot and was subsequently passaged 9 times in MRC-5 cells, and P-Oka was passaged 14 times in MRC-5 cells prior to use in this study. The array of mutations in V-Oka, which demonstrates 27 sites of sequence polymorphism (9), indicates that the virus preparation is not a pure virus strain but co...

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Section: Discussionmentioning

confidence: 77%

Comparison of Virus Transcription during Lytic Infection of the Oka Parental and Vaccine Strains of Varicella-Zoster Virus

Cohrs¹,

Gilden

Gomi

et al. 2006

J Virol

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“…Three observations suggest that the SNPs reported here may not be solely responsible for the ability of virus to replicate in the skin and that virus present in the skin is still highly attenuated. First, a study using chimeric viruses containing portions of the vaccine and parental Oka virus indicated that growth of the virus in human skin is caused by differences at multiple sites throughout the genome, especially in genes 30-55 (20). The VZV SNPs that differed between the vaccine rashes and the vaccine batches in the current study (1) were in genes 51 and 62 and between genes 61 and 62.…”

mentioning

confidence: 65%

“…The VZV SNPs that differed between the vaccine rashes and the vaccine batches in the current study (1) were in genes 51 and 62 and between genes 61 and 62. However, cloned vaccine virus was used in the study with the chimeras (20) so that it did not have the polymorphic features of the vaccine virus; at least one SNP (nucleotide 105,356) in the cloned virus had the parental sequence rather than the sequence that is more prevalent in vaccine batches. Second, because virus transmitted from rashes in vaccinees to secondary cases remains highly attenuated, the SNPs that are more highly represented in vaccine rashes than in vaccine batches, are not associated with increased virulence.…”

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confidence: 99%

Varicella-zoster vaccine virus: Evolution in action

Cohen

2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Yet studies of IE62 promoter activity with constructs containing various mutations within IE62 have shown only modest deficits in function evaluated in vitro (5). Further, recombinant chimeric viruses made from cosmids consisting of parental and vaccine Oka segments have not defined specific ORF62 SNPs associated with altered replication in vitro (29,38). These experiments showed that chimeric viruses with various segments from vOka were attenuated, independently of ORF62.…”

Section: Discussionmentioning

confidence: 99%

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

Peters

Tyler

Carpenter

et al. 2012

J Virol

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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.

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Analysis of varicella zoster virus attenuation by evaluation of chimeric parent Oka/vaccine Oka recombinant viruses in skin xenografts in the SCIDhu mouse model

Cited by 53 publications

References 35 publications

Comparison of Virus Transcription during Lytic Infection of the Oka Parental and Vaccine Strains of Varicella-Zoster Virus

Comparison of Virus Transcription during Lytic Infection of the Oka Parental and Vaccine Strains of Varicella-Zoster Virus

Varicella-zoster vaccine virus: Evolution in action

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

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