Antigenic Variation of Varicella Zoster Virus Fc Receptor gE: Loss of a Major B Cell Epitope in the Ectodomain

Abstract

Varicella zoster virus (VZV) is considered to possess a genetically stable genome; only one serotype is recognized around the world. The 125-kbp genome contains approximately 70 open reading frames. One that has received particular attention is open reading frame 68, which codes for glycoprotein gE, the predominant 623-residue viral envelope product that harbors both B and T cell epitopes. This report describes the initial characterization of a community-acquired VZV isolate that was a distinguishable second serotype (i.e., it had lost a major B cell epitope defined on the gE ectodomain by a murine monoclonal antibody called mAb 3B3). The mAb 3B3 epitope was found not only on the prototype sequenced Dumas strain from Holland and all previously tested North American isolates but also on the varicella vaccine Oka strain originally attenuated in Japan. Sequencing of the mutated gE ectodomain demonstrated that codon 150 exhibited a single base change that led to an amino acid change (aspartic acid to asparagine). Observation of the monolayers infected with the mutant VZV strain also led to the surprising discovery that the topography of egress was altered. Wild-type VZV emerges along distinctive viral highways, whereas the mutant strain virions were nearly uniformly distributed over the cell surface in a pattern more closely resembling egress of herpes simplex virus 1. The mutant VZV strain was designated VZV-MSP because it was isolated in Minnesota.

Incorporation of Three Endocytosed Varicella-Zoster Virus Glycoproteins, gE, gH, and gB, into the Virion Envelope

“…Propagation of the VZV-32 strain (GenBank accession no. AH010537) was performed as previously described (24,54). Monolayers inoculated with VZV-infected cells were processed 24 or 48 h postinfection (hpi) as described below.…”

“…Both the ectodomain and the endodomain of gE have important functions. Based on the fact that a single point mutation in the VZV-MSP gE ectodomain changes the VZV-MSP egress pattern from a typical "viral highway" phenotype to a diffuse pattern similar to that observed in HSV-1-infected cells (53,54), the ectodomain is likely to be critical for determining virus-cell interactions of mature virions.…”

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

“…First, we describe a severe and atypical varicella in an immunocompetent host. Second, as already suggested (Santos et al, 1998) it appears of great interest to address the role of antibodies in VZV primary infection.…”

“…Moreover, higher morbidity from varicella is described during pregnancy and adulthood, although the reasons for this are unclear. Recently, two mutant viruses able to elude immune detection were described (Santos et al, 1998;Tipples et al, 2002). 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.…”

“…Despite such evidence, the pathogenic mechanisms underlying these complications are largely unknown. Recently, mutations of VZV DNA have been described in immunodepressed patients, although not associated with severe clinical manifestations (Santos et al, 1998;Tipples et al, 2002). We describe a case of acute, lethal liver failure in a healthy 15-year-old boy with VZV infection.…”