APOBEC3-driven attenuation of the 2022 global outbreak monkeypox virus relative to its clade IIb ancestor

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 microevolution1-3. 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 APOBEC 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.