APOBEC3-driven attenuation of the 2022 global outbreak monkeypox virus relative to its clade IIb ancestor
7 affiliations
- 1Department of Infectious Diseases, King's College London, London, UK
- 2Department of Microbial Sciences, University of Surrey, Guildford, UK
- 3Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, Spain
- 4The Pirbright Institute, Pirbright, UK
- 5Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
- 6CBR Division, Defence Science and Technology Laboratory, Salisbury, UK
- 7Department of Microbial Sciences, University of Surrey, Guildford, UK. [email protected]
Abstract
Monkeypox virus (MPXV) is a zoonotic virus endemic to Africa that has recently re-emerged, becoming the first orthopoxvirus with sustained human-to-human transmission since smallpox eradication. The 2022 global epidemic of MPXV was caused by Clade IIb virus (lineage B.1) that derived from the lineage A endemic to West Africa through APOBEC3 microevolution 1–3 . Here, comparison of lineage B.1 virus with its closest earlier A.1 ancestor reveals that despite only 46 nucleotide differences, lineage B.1 has attenuating phenotypic changes. Both viruses replicated equivalently in cell culture, but B.1 had defects in long-range spread, which mapped to APOBEC3 mutation E353K in OPG057 (F13L). MPXV B.1 was also defective in innate immune control, inducing higher IFNβ and innate immune signalling gene expression, and showing reduced capacity to suppress interleukin-1β-mediated responses, which mapped to APOBEC3 mutation R48C in OPG047 (F3L). Finally, MPXV B.1 had reduced virulence in a mouse model of MPXV infection relative to the ancestral A.1 strain. Our work demonstrates that the 2022 global outbreak MPXV was intrinsically attenuated, with attenuating mutations that are absent in concurrent, more severe clade IIb outbreaks. Our data also reveal that APOBEC3 editing is a mechanism of MPXV phenotypic variation, potentially contributing to clade evolution and competition.
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BibTeX
@article{sumner2026apobec3driven,
title = {{APOBEC3-driven attenuation of the 2022 global outbreak monkeypox virus relative to its clade IIb ancestor}},
author = {Rebecca P. Sumner and Lucy Eke and Bruno Hernáez and Alasdair J. M. Hood and Telma M Sancheira Freitas and Hannah Ashby and Ailish Ellis and Marine J. Petit and Sian Lant and Isobel Stokes and Preetam Parija and Isabel Alonso-Sánchez and Francisco Javier Alvarez-de Miranda and Alazne R. Unanue and Kevin Maringer and Isabelle Dietrich and Bryan Charleston and Geoffrey L. Smith and David Ulaeto and Antonio Alcamı́ and Carlos Maluquer de Motes},
journal = {Nature Communications},
year = {2026},
month = aug,
doi = {10.1038/s41467-026-76580-7},
url = {https://doi.org/10.1038/s41467-026-76580-7},
note = {CC BY},
}
RIS
TY - JOUR
TI - APOBEC3-driven attenuation of the 2022 global outbreak monkeypox virus relative to its clade IIb ancestor
AU - Rebecca P. Sumner
AU - Lucy Eke
AU - Bruno Hernáez
AU - Alasdair J. M. Hood
AU - Telma M Sancheira Freitas
AU - Hannah Ashby
AU - Ailish Ellis
AU - Marine J. Petit
AU - Sian Lant
AU - Isobel Stokes
AU - Preetam Parija
AU - Isabel Alonso-Sánchez
AU - Francisco Javier Alvarez-de Miranda
AU - Alazne R. Unanue
AU - Kevin Maringer
AU - Isabelle Dietrich
AU - Bryan Charleston
AU - Geoffrey L. Smith
AU - David Ulaeto
AU - Antonio Alcamı́
AU - Carlos Maluquer de Motes
PY - 2026
DA - 2026/08/11
JO - Nature Communications
DO - 10.1038/s41467-026-76580-7
UR - https://doi.org/10.1038/s41467-026-76580-7
AB - Monkeypox virus (MPXV) is a zoonotic virus endemic to Africa that has recently re-emerged, becoming the first orthopoxvirus with sustained human-to-human transmission since smallpox eradication. The 2022 global epidemic of MPXV was caused by Clade IIb virus (lineage B.1) that derived from the lineage A endemic to West Africa through APOBEC3 microevolution 1–3 . Here, comparison of lineage B.1 virus with its closest earlier A.1 ancestor reveals that despite only 46 nucleotide differences, lineage B.1 has attenuating phenotypic changes. Both viruses replicated equivalently in cell culture, but B.1 had defects in long-range spread, which mapped to APOBEC3 mutation E353K in OPG057 (F13L). MPXV B.1 was also defective in innate immune control, inducing higher IFNβ and innate immune signalling gene expression, and showing reduced capacity to suppress interleukin-1β-mediated responses, which mapped to APOBEC3 mutation R48C in OPG047 (F3L). Finally, MPXV B.1 had reduced virulence in a mouse model of MPXV infection relative to the ancestral A.1 strain. Our work demonstrates that the 2022 global outbreak MPXV was intrinsically attenuated, with attenuating mutations that are absent in concurrent, more severe clade IIb outbreaks. Our data also reveal that APOBEC3 editing is a mechanism of MPXV phenotypic variation, potentially contributing to clade evolution and competition.
SN - 2041-1723
ER -