A new analysis shows that the monkeypox, or mpox, virus is rapidly diverging into several lineages characterized by mutations resulting from continued interaction with the human immune system, suggesting that the virus 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,” write the authors. Historically, MPXV was described as a zoonotic disease endemic to West and Central Africa that transmits through contact with rodents. The first human cases of the disease were observed in the 1970s and have been predominantly associated with infants and children. Most cases since have largely been treated as independent spillover events with low levels of circulation in the human population. However, in 2022, an international MPXV epidemic emerged and human mpox cases were detected outside countries with known endemic reservoirs, indicating that it was not solely a zoonotic infection. Comparisons of MPXV genome sequences from 2018 with sequences from the 2022 epidemic have indicated a mutation rate much higher than would be expected for double-stranded DNA viruses. Most mutations were dinucleotide changes characteristic of activity by an antiviral enzyme in the human immune system called APOBEC3, signaling sustained human-to-human mpox transmission rather than repeated zoonotic spillover. To address this, Áine O’Toole and colleagues developed a molecular clock method to evaluate the evolution of MPXV. The findings confirm that the now globally distributed B.1 lineage of human mpox displays many mutations signaling APOBEC3 exposure and that this APOBEC3-driven evolution is a signature of a switch to sustained transmission within the human population. Moreover, assuming a rate of ~6 APOBEC3 mutations per year, O’Toole et al. estimate that the recent MPXV clade IIb has been circulating in humans since at least 2016. “Although the B.1 lineage across the world is now diminished – though not yet eradicated – the human epidemic from which it arose continues unabated,” write O’Toole et al. “Surveillance needs to be global if MPXV is to be eliminated from the human population and then prevented from reemerging.”

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