Synthetic genome shuffling of poxviruses in yeast generates novel poxvirus candidates with potential oncolytic properties.
- 1Transgene, Illkirch-Graffenstaden, France.
Abstract
Oncolytic viruses represent a promising class of biotherapeutics, yet their clinical performance is often constrained by limited cytolytic potency and insufficient immune activation. To address these limitations, we developed a synthetic biology framework that applies genome-scale recombination in yeast to generate chimeric poxviruses derived from multiple non-human-pathogenic poxvirus lineages. We first established the near-complete assembly of a vaccinia virus genome within yeast and demonstrated its ability to yield a functional virus in human cancer cells, providing a modular foundation for genome engineering. Building on this platform, we combined genomic inputs from different poxvirus species to create a diverse library of chimeric constructs, a subset of which could be recovered as infectious particles. Phenotypic characterization revealed substantial variation among chimeras, including distinct plaque morphologies, spreading behaviors, and activity across human cancer cell lines, indicating the emergence of functional diversity rather than incremental modification. Whole-genome sequencing confirmed that individual chimeras integrated genetic segments from several parental species, validating the broad recombination capacity of the yeast-based system. Collectively, these results establish a conceptual advance in synthetic virology. Yeast-mediated genome shuffling enables the rapid generation of functionally diverse chimeric poxviruses from multispecies inputs, providing a flexible and scalable platform for the identification and development of future oncolytic poxvirus candidates. While the chimeric viruses described here do not yet contain the attenuating mutations required for tumor-selective replication, they provide a foundation for the engineering of next-generation oncolytic biotherapeutics.
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BibTeX
@article{agaoua2026synthetic,
title = {{Synthetic genome shuffling of poxviruses in yeast generates novel poxvirus candidates with potential oncolytic properties.}},
author = {Aimeric Agaoua and Camille Rey and Julie Hortelano and Anne-Isabelle Moro and Benoit Grellier and Philippe Erbs},
journal = {Frontiers in bioengineering and biotechnology},
year = {2026},
month = oct,
doi = {10.3389/fbioe.2026.1943548},
url = {https://europepmc.org/article/MED/42953098},
note = {CC BY},
}
RIS
TY - JOUR
TI - Synthetic genome shuffling of poxviruses in yeast generates novel poxvirus candidates with potential oncolytic properties.
AU - Aimeric Agaoua
AU - Camille Rey
AU - Julie Hortelano
AU - Anne-Isabelle Moro
AU - Benoit Grellier
AU - Philippe Erbs
PY - 2026
DA - 2026/10/14
JO - Frontiers in bioengineering and biotechnology
DO - 10.3389/fbioe.2026.1943548
UR - https://europepmc.org/article/MED/42953098
AB - Oncolytic viruses represent a promising class of biotherapeutics, yet their clinical performance is often constrained by limited cytolytic potency and insufficient immune activation. To address these limitations, we developed a synthetic biology framework that applies genome-scale recombination in yeast to generate chimeric poxviruses derived from multiple non-human-pathogenic poxvirus lineages. We first established the near-complete assembly of a vaccinia virus genome within yeast and demonstrated its ability to yield a functional virus in human cancer cells, providing a modular foundation for genome engineering. Building on this platform, we combined genomic inputs from different poxvirus species to create a diverse library of chimeric constructs, a subset of which could be recovered as infectious particles. Phenotypic characterization revealed substantial variation among chimeras, including distinct plaque morphologies, spreading behaviors, and activity across human cancer cell lines, indicating the emergence of functional diversity rather than incremental modification. Whole-genome sequencing confirmed that individual chimeras integrated genetic segments from several parental species, validating the broad recombination capacity of the yeast-based system. Collectively, these results establish a conceptual advance in synthetic virology. Yeast-mediated genome shuffling enables the rapid generation of functionally diverse chimeric poxviruses from multispecies inputs, providing a flexible and scalable platform for the identification and development of future oncolytic poxvirus candidates. While the chimeric viruses described here do not yet contain the attenuating mutations required for tumor-selective replication, they provide a foundation for the engineering of next-generation oncolytic biotherapeutics.
SN - 2296-4185
ER -