Complete DNA Sequence Analyses of the First Two Varicella-Zoster Virus Glycoprotein E (D150N) Mutant Viruses Found in North America: Evolution of Genotypes with an Accelerated Cell Spread Phenotype

Abstract

Varicella-zoster virus (VZV) is considered to be one of the most genetically stable of all the herpesviruses.Yet two VZV strains with a D150N missense mutation within the gE glycoprotein were isolated in North America in 1998 and 2002. The mutant strains have an accelerated cell spread phenotype, which distinguishes them from all wild-type and laboratory viruses. Since the VZV genome contains 70 additional open reading frames (ORFs), the possibility existed that the phenotypic change was actually due to an as-yet-undiscovered mutation or deletion elsewhere in the genome. To exclude this hypothesis, the entire genomes of the two mutant viruses were sequenced and found to contain 124,883 (VZV-MSP) and 125,459 (VZV-BC) nucleotides. Coding single-nucleotide polymorphisms (SNPs) were identified in 14 ORFs. One missense mutation was discovered in gH, but none was found in gB, gI, gL, or gK. There were no coding SNPs in the major regulatory protein ORF 62. One polymorphism was discovered which could never have been anticipated based on current knowledge of herpesvirus genomics, namely, the origins of replication differed from those in the prototype strain but not in a manner expected to affect cell spread. When the two complete mutant VZV sequences were surveyed in their entirety, the most reasonable conclusion was that the increased cell spread phenotype was dependent substantially or solely on the single D150N polymorphism in glycoprotein gE. The genomic results also expanded the evolutionary database by identifying which VZV ORFs were more likely to mutate over time.

Complete-Genome Phylogenetic Approach to Varicella-Zoster Virus Evolution: Genetic Divergence and Evidence for Recombination

“…Strains 123 (previously named 123J) and DR (previously named Morocco 1) were selected as representative strains for the genotypes M1 and M2, respectively, and were sequenced at the National VZV Laboratory at the Centers for Disease Control and Prevention (25). Sequence data for four additional VZV strains were obtained from GenBank (BC, gi 46981409; Dumas, gi 9625875 [or 59989, older entry]; MSP, gi 46981482; and parental Oka [P-Oka], gi 26665420) and have been described previously (8,17). The culture-attenuated vaccine preparation (V-Oka, gi 2264274) was also included in the phylogenetic analyses of complete genomic sequences.…”

A novel mutation of varicella-zoster virus associated to fatal hepatitis

“…These two strains bear a mutation (D150N) in the predominant glycoprotein specified in infected cells and virions (gE) that leads to the loss of a Bcell epitope. These mutant viruses grow more rapidly in cell culture than the wild type (Grose et al, 2004). Likewise, in the SCID-hu mouse (severe combined immunodeficient mouse with human skin implant) infection proceeds with increased virulence (Santos et al, 2000).…”

An Sp1/Sp3 Site in the Downstream Region of Varicella-Zoster Virus (VZV) oriS Influences Origin-Dependent DNA Replication and Flanking Gene Transcription and Is Important for VZV Replication In Vitro and in Human Skin

“…VZV strain MSP (VZV-MSP) (11) and VZV strain pOka (10) were propagated in MeWo cell monolayers, as described previously by Lynch et al (22) and Peng et al (32).…”