Reacción a "Reaction to monkeypox genome analysis of monkeypox virus from patients in the current outbreak"

The authors of the study belong to several Portuguese teams from the Portuguese national health institute. They have sequenced the available genomes of the monkeypox virus isolated during the 2022 outbreak and analysed them together with all available sequences. The virus from the 2022 outbreak is very close to a virus that appeared in 2018 and 2019 in Nigeria, and was then exported to the UK, Israel and Singapore.

The researchers propose that the most likely hypothesis is that the virus would have continued to circulate and evolve endemically in Nigeria, and from there would have been exported again.

The results show that the first confirmed case in the UK is probably not the first case of the virus being exported out of Nigeria in this outbreak. The most likely scenario is that the virus has been circulating since 2017 in Nigeria (prior to this outbreak, WHO had identified more than 500 suspected cases in Nigeria in the past five years), and that this outbreak we are now seeing is the result of one or more events of export of the virus from Nigeria, very close in time, with a superdiseminating event (e.g. in saunas or through sexual contact), associated with rapid geographical spread.

This outbreak is particular because of the number of mutations that the sequenced genomes have accumulated. The simian pox virus is an orthopoxvirus. Orthopoxviruses are viruses with a genome with two DNA strands, like our cells. They are viruses with large genomes (more than six times longer than the SARS-CoV-2 genome), very stable, and code for about 200 proteins. They evolve slowly because when the genome is copied, the molecular machinery does not make many mistakes and does not introduce many mutations. However, the sequenced genomes of the current outbreak show many changes, about ten times more than expected given the type of virus we are talking about.

Moreover, these changes preferentially go in one direction, that of converting C to T (using the letters commonly used in genetics). This type of directional change is common in the evolution of many viruses, but the most important thing is that it is not the viruses that cause them, but human proteins that cause the virus to accumulate mutations.

These are enzymes called APOBEC3, produced by host cells, which in principle have an antiviral function (introducing mutations into viruses to inactivate them), but which can have the effect of accelerating the rate of virus mutation. In fact, the action of APOBEC3 enzymes is responsible for the accumulation of many C to T mutations in other viruses, such as HIV, SARS-CoV-2 or human papillomaviruses.

It is very important to say that the repertoire of APOBEC3 enzymes in the human genome is very varied, that it depends on the ancestry and genetic background of each person, and that each cell type in our body can express different types of APOBEC3. This greatly complicates the study and fragments the evolution of viruses, because by infecting different people of different ancestry, a viral lineage may evolve differently; and because by infecting different tissues (skin, muscle, liver) it will also evolve differently.

This is probably what may have happened in the case of this outbreak, and is what the Portuguese researchers propose: this virus jumped into humans in 2019 in Nigeria and has been in uninterrupted human-to-human transmission ever since, has undergone very significant directional mutational pressures from C to T, and has also undergone very strong selection pressures to adapt to human-to-human transmission.

This would have resulted in the accumulation of mutations that may have facilitated effective human-to-human transmission of the virus and led to this outbreak, which has now generated more than 1,700 WHO-confirmed cases across Europe, according to the European Centre for Disease Prevention and Control (ECDC).