O’Toole, ÁineNeher, Richard A.Ndodo, NnaemekaBorges, VitorGannon, BenGomes, João PauloGroves, NatalieKing, David J.Maloney, DanielLemey, PhilippeLewandowski, KuiamaLoman, NicholasMyers, RichardOmah, Ifeanyi F.Suchard, Marc A.Worobey, MichaelChand, MeeraIhekweazu, ChikweUlaeto, DavidAdetifa, IfedayoRambaut, Andrew2024-01-222024-01-222023-11-03Science. 2023 Nov 3;382(6670):595-600. doi: 10.1126/science.adg8116. Epub 2023 Nov 2.0036-8075http://hdl.handle.net/10400.18/8947Historically, mpox has been characterized as an endemic zoonotic disease that transmits through contact with the reservoir rodent host in West and Central Africa. However, in May 2022, human cases of mpox were detected spreading internationally beyond countries with known endemic reservoirs. When the first cases from 2022 were sequenced, they shared 42 nucleotide differences from the closest mpox virus (MPXV) previously sampled. Nearly all these mutations are characteristic of the action of APOBEC3 deaminases, host enzymes with antiviral function. Assuming APOBEC3 editing is characteristic of human MPXV infection, we developed a dual-process phylogenetic molecular clock that-inferring a rate of ~6 APOBEC3 mutations per year-estimates that MPXV has been circulating in humans since 2016. These observations of sustained MPXV transmission present a fundamental shift to the perceived paradigm of MPXV epidemiology as a zoonosis and highlight the need for revising public health messaging around MPXV as well as outbreak management and control.Editor’s summary: In March 2022, an international epidemic of human Mpox was detected, showing that it was not solely a zoonotic infection. A hallmark of the approximately 88,000 cases that have been reported were TC>TT and GA>AA mutations in Mpox viruses, which were acquired at a surprisingly high evolutionary rate for a pox virus. Knowing that these types of mutation are a sign of activity by a host antiviral enzyme called APOBEC3, O’Toole et al. investigated whether the mutations reflected human-to-human transmission rather than repeated zoonotic spillover. Bayesian evolutionary analysis showed that Mpox virus recently diversified into several lineages in humans that display elevated numbers of mutations, signaling APOBEC exposure and sustained human-to-human transmission rather than zoonosis as the source of new cases. —Caroline AshengMpox VirusMonkeypox VirusGeneticsEpidemiologyTransmissionMutationPhylogenyAPOBEC DeaminasesHuman MPXV infectionInfecções Emergentesjournal article10.1126/science.adg8116