Fixed Nonsynonymous vOka Mutations in IE62 Drive Varicella-Zoster Virus Attenuation in Human Skin
- 1SUNY Upstate Medical University
Abstract
The live, attenuated vaccine for Varicella-Zoster Virus (VZV) protects against chickenpox in children and adults. However, the vaccine strain Oka (vOka) establishes latency and may reactivate. The molecular basis of vOka attenuation remains unknown. We investigated whether three high-frequency single-nucleotide polymorphisms (SNPs) that differentiate vOka from parental strain Oka (pOka) are responsible: S628G and R958G in the immediate-early regulatory protein IE62, and *130R in the membrane protein ORF0. We evaluated how these fixed SNPs mediate the attenuated growth phenotype of VZV and diminish skin pathology by creating recombinant pOka VZV carrying these SNPs in the wild-type background. These were assessed in cells and human skin organ cultures (SOCs). In epithelial and fibroblast cell lines, the individual IE62 mutations slightly delayed viral growth at 8 - 24 hours post-infection but not in human epidermal keratinocytes (htert-HEK). The fixed ORF62 SNPs also affected ORF62 transcription, IE62 protein abundance at early times, and delayed IE62 accumulation in the cytoplasm later during infection. The *130R mutation in ORF0 conferred a growth advantage in culture, suggesting it is an adaptation to cell culture. While there was donor-to-donor variability and differences in overall virus spread in SOC, the R958G and *130R conferred an attenuated growth phenotype similar to that of vOka in SOC. Histopathologic analysis of VZV-infected skin sections revealed that, similar to vOka, S628G and R958G in IE62 limited the spread of VZV skin lesions. Our findings underscore the critical roles of conserved vOka SNPs in understanding the attenuation of the live vaccine strain vOka.
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BibTeX
@misc{onwe2026fixed,
title = {{Fixed Nonsynonymous vOka Mutations in IE62 Drive Varicella-Zoster Virus Attenuation in Human Skin}},
author = {R. Onwe and J. Ramos Ferreira and M. G. Lloyd and J. Flot and P. R. Kinchington and J. F. Moffat},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.754941},
url = {https://www.biorxiv.org/content/10.64898/2026.09.28.754941v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Fixed Nonsynonymous vOka Mutations in IE62 Drive Varicella-Zoster Virus Attenuation in Human Skin
AU - R. Onwe
AU - J. Ramos Ferreira
AU - M. G. Lloyd
AU - J. Flot
AU - P. R. Kinchington
AU - J. F. Moffat
PY - 2026
DA - 2026/09/28
PB - bioRxiv
DO - 10.64898/2026.09.28.754941
UR - https://www.biorxiv.org/content/10.64898/2026.09.28.754941v1
AB - The live, attenuated vaccine for Varicella-Zoster Virus (VZV) protects against chickenpox in children and adults. However, the vaccine strain Oka (vOka) establishes latency and may reactivate. The molecular basis of vOka attenuation remains unknown. We investigated whether three high-frequency single-nucleotide polymorphisms (SNPs) that differentiate vOka from parental strain Oka (pOka) are responsible: S628G and R958G in the immediate-early regulatory protein IE62, and *130R in the membrane protein ORF0. We evaluated how these fixed SNPs mediate the attenuated growth phenotype of VZV and diminish skin pathology by creating recombinant pOka VZV carrying these SNPs in the wild-type background. These were assessed in cells and human skin organ cultures (SOCs). In epithelial and fibroblast cell lines, the individual IE62 mutations slightly delayed viral growth at 8 - 24 hours post-infection but not in human epidermal keratinocytes (htert-HEK). The fixed ORF62 SNPs also affected ORF62 transcription, IE62 protein abundance at early times, and delayed IE62 accumulation in the cytoplasm later during infection. The *130R mutation in ORF0 conferred a growth advantage in culture, suggesting it is an adaptation to cell culture. While there was donor-to-donor variability and differences in overall virus spread in SOC, the R958G and *130R conferred an attenuated growth phenotype similar to that of vOka in SOC. Histopathologic analysis of VZV-infected skin sections revealed that, similar to vOka, S628G and R958G in IE62 limited the spread of VZV skin lesions. Our findings underscore the critical roles of conserved vOka SNPs in understanding the attenuation of the live vaccine strain vOka.
ER -