Turning Tides

Mpox has historically been regarded as a zoonotic disease, but, in May 2022, the virus started to spread internationally in non-endemic countries. Now, researchers have found evidence to suggest that mpox capable of human-to-human transmission has been circulating since 2016 (1). We spoke with lead researcher Áine O’Toole to find out more.

What led you to investigate the change in mpox transmission from zoonotic spillover to sustained human-to-human transmission?

Our lab works on emerging outbreaks of (usually) RNA viruses because they evolve very quickly and measurably evolve over the course of a relatively short outbreak. Mpox virus (MPXV) is a DNA virus, which usually evolves much slower; however, the early sequences from this outbreak showed unusually high numbers of mutations. When we looked at the data, it was really striking that most of these mutations seemed to be of a particular type (TC->TT), and that this mutation pattern fit with the mutation profile of APOBEC3 editing.

What were the main findings of your study?

Harnessing the mutations that had occurred across the current outbreak of MPXV, we created a phylogenetic model that represented the ongoing dual process – the background evolution of the virus and the specific action of APOBEC3 on the virus population – and estimated that the virus has been circulating in the human population since at least 2016 (when we estimate the initial zoonosis occurred).

Could you tell us more about APOBEC3 and the mutations it induces?

APOBEC3 is a family of host (human) enzymes that have anti-viral functionality and mutate the virus in an attempt to attenuate its ability to transmit. Sometimes it might be successful and introduce enough mutations to the viral genome that it can no longer replicate, but sometimes it is not successful and the virus can continue to transmit. The APOBEC3-type mutations we observe in the MPXV genomes throughout this outbreak seem to, on average, accumulate at about six per year. We calculate this by building a phylogenetic tree of the outbreak using viral genomes sampled and sequenced from mpox patients. We can reconstruct the mutations that occurred across this tree on each branch. By counting how many APOBEC3 mutations had occurred between the root of the tree and each sample tip, and plotting it against the date of sampling, we can create an APOBEC3 “clock.” The slope of the regression line for this clock is the rate, which gives about six mutations per year.

How might your findings impact public health policy and messaging for managing and controlling the spread of mpox?

MPXV has historically been regarded as a primarily zoonotic virus with limited capacity for human-to-human transmission. In 2022, the expansion of the global B.1 lineage of MPXV Clade IIb demonstrated that this paradigm needed to be re-evaluated, as we observed sustained human-to-human transmission. Here, we have shown that this switch to human-to-human transmission likely occurred much earlier – and that the virus has been circulating in the human population since that time.

As APOBEC3 mutations appear to be a hallmark of human-to-human transmission of MPXV, we could use the presence of an excess of APOBEC3 mutations to infer if the virus has been circulating undetected in humans in novel outbreaks. In the UK, whether the virus is part of the current outbreak or a novel zoonosis will impact public health and infection control policies, so having an easy way to distinguish this may be very useful.