On April 29, 2022, a British citizen developed a rash while traveling in Nigeria, Africa. Upon returning to the UK, he decided to go to hospital as his rash worsened, his lymph nodes swollen and his fever rose. There they confirmed that it was monkeypox (or mpox, as the World Health Organization, WHO, renamed it). It is a disease of zoonotic origin caused by a virus that occasionally jumps from some animals and which until then had difficulty transmitting between humans. But in just one month, there were thousands of cases in Spain, Portugal, the United States, Colombia, Singapore… The WHO was forced to declare an international public health emergency. Now, work by top-level virologists has discovered that the strain causing the outbreak had been circulating among humans for several years. They have also proven that a human enzyme with antiviral activity would have accelerated the mutation rate of the pathogen and this worries scientists, who fear that mpox will remain among us.
Today, the threat of the virus has been reduced. Although there are still new infections, the WHO withdrew its alert in the summer. But the pathogen is still there and it is still unknown where it emerged from. In the past, outbreaks have always had the same characteristics, a jump from animal to human, usually a rodent (its best-known reservoir) or an ape, followed by a few human-to-human infections. The virus did not adapt well to the human environment. But something must have changed in 2022, when in just a few months thousands of people were infected (at the end of October 2023, there were already more than 91,000 people). Most had never traveled to countries where mpox is endemic, such as Nigeria or the Democratic Republic of the Congo, so there was sustained human-to-human transmission over time, something that does not fit with a zoonotic disease.
Now, a large and renowned group of scientists, including some of those who first characterized SARS-Cov-2 after the coronavirus pandemic, have sequenced the genome of almost a hundred samples of the virus, with some dating back to to the 60s of the last century. They wanted to know where and when the lineage that caused the 2022 outbreak, named B.1, emerged. This mpox is grouped in the so-called clade IIb, whose origin is in the West African region. Fortunately, its lethality is 10 times lower than that of clade II viruses, endemic to the center of the African continent.
The results of this research, published today in the prestigious scientific journal Science, points out that the 2022 samples are not the first of the outbreak: they share up to 42 mutations in their DNA, the tracing of which took them to a case from 2015, which already had one of these changes. The following year, Nigerian authorities reported some cases of mpox in humans, but they were then thought to be of zoonotic origin, jumping from animals, and not related to each other. They were wrong. Already then, in 2016, the researchers conclude in their work, “the virus was circulating sustainably among humans.”
“It is unclear what led to the global spread of B.1. There doesn’t seem to be anything particularly different about this virus, in this lineage.”
Áine O’Toole, virologist at the University of Edinburgh (United Kingdom)
To support this conclusion, they rely on the origin of those 42 changes in the viral DNA. They focused on nucleotides, the four fundamental elements of DNA, known by the letters A, T, G and C. They then verified that practically all of these mutations appear related to the action of an enzyme, APOBEC3. Present in almost all mammals, rodents, the supposed reservoirs of the virus, only have one copy that they express in the spleen and bone marrow and not in other tissues. In humans it is part of the immune system. Its mission is to remove portions of the virus’s DNA that complicate its replication. In all cases from 2017 onwards these genetic modifications appear, which would rule out that the changes had occurred before the virus jumped from animals to humans.
The first author of the research, the virologist from the University of Edinburgh (United Kingdom), Áine O’Toole tells it: “Since it spread to the human population (we estimate that it was at least in 2016), the traces of the edition of APOBEC3 are seen as scars on the virus genome.” When these viruses begin their replication, they reveal their DNA, an opportunity that this enzyme takes advantage of to change some letters for others. In most cases, this interferes with its replicative machinery, but in other cases, the pathogen manages to replicate, already with the APOBEC3 mark. What O’Toole does not have an answer for is the timing of the outbreak, why did it break out in May 2022 when it had been circulating for at least six years? “It is unclear what led to the global spread of B.1. There doesn’t seem to be anything particularly different about this virus, this lineage; Most likely, it had the opportunity to spread widely because it entered certain population networks.”
Antonio Alcamí, virologist at the Severo Ochoa Molecular Biology Center (CMB/CSIC) highlights how important it is to know when it began to circulate: “It was believed that it was recent, but since 2016 and in humans, the virus has the same brand as that of the 2022 outbreak.” For Alcamí, not related to the work published in Science, their findings are very relevant. “It was thought that mpox did not adapt to humans, but if we now see that it has been infecting people for years, this would be a warning that it is adapting to humans.”
“The longer it has been circulating among humans, the greater the likelihood that the virus will become more human”
Raúl Rivas, professor of microbiology and genetics at the University of Salamanca
One of the keys could be that APOBEC3 has accelerated the rate of mutation of the virus. From what was known from other orthopoxviruses, such as human smallpox, and previous samples, the rate of change of mpox was very low. However, in two or three years it accumulated 42 changes in its DNA, which is equivalent to a 28 times faster rate of the B.1 lineage than the previous ones. “The key thing here is to know if these mutations affect greater transmissibility between humans,” highlights the professor of microbiology and genetics at the University of Salamanca, Raúl Rivas, who also highlights the dating of the first cases with these mutations: “The more “The longer it has been circulating among humans, the greater the likelihood that the virus will become more human.”
The authors clarify and the experts consulted confirm that the fact that this antiviral enzyme is behind the mutations present in the B.1 lineage does not mean that APOBEC3 is increasing the ability of the virus to replicate and transmit between humans. The professor at the University of Valencia and dedicated to the phylogenomics and evolution of viruses highlights this: “APOBEC3 is not the cause, but it is mutagenic and among the mutations that have emerged, some have allowed greater transmissibility of the virus.” What remains to be done is to connect the antiviral enzyme with this greater contagion capacity. And this is something that is urgent.
In their conclusions, the authors of the study propose that, if a link is found between APOBEC3 and the persistence of mpox for years among humans, it would be a paradigm shift. Oriol Mitjà, from the Germans Trias i Pujol Hospital in Barcelona, agrees with this and participated in the discovery of a fulminant form of monkeypox in people with advanced HIV. “In the future, there will be new zoonotic outbreaks, but if this transmission between humans continues, we could say that it is already a human virus. It is, as happened with HIV [también zoonótico inicialmente]a paradigm shift,” he adds.
For the experts consulted, what has been discovered now adds urgency to the concern that already existed since that British man was diagnosed. The vast majority of the more than 91,000 infected so far are under 50 years of age. That is, they were not vaccinated against smallpox, eradicated from the planet in 1980. There is a risk that mpox will occupy the niche of its viral relative and do so among an unimmunized population. It could still be worse. If the B.1 lineage manages to transmit between humans, so could clade I viruses, which kill 10 people out of every 100 infected.
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