Striking mutations: fresh results from HUN-REN researchers in Szeged could aid the development of new vaccines

During the COVID-19 pandemic, an enormous amount of genetic data was collected on SARS-CoV-2, giving researchers a rare chance to track in detail how the virus has changed over time. Earlier studies found that some SARS-CoV-2 mutations help the virus evade immune detection, essentially making it “invisible.” This new study, however, observed the opposite effect through a specific mechanism. The HUN-REN researchers argue that a significant share of the mutations appearing in the virus’s genetic material are caused by the body’s so-called APOBEC molecules. 

APOBEC enzymes are part of the early, non-specific immune response and can alter the genetic code of viruses. What’s more, the study suggests that the mutations they cause don’t usually weaken the body’s defenses, they actually strengthen the immune response later on. That’s because they create protein changes the immune system can detect more easily, meaning a fast initial response helps the later, targeted immune response work more effectively. 

A substantial share of SARS-CoV-2 mutations were not created by chance, but by APOBEC3 enzymes, a family of proteins in the human immune system that plays an important role in defense. These enzymes chemically alter the virus’s genetic material, swapping the building block cytosine (C) for uracil (U), which in turn changes the virus’s proteins.

The researchers analyzed the proteins of several thousand SARS-CoV-2 variants and found that mutations linked to APOBEC lead to better HLA binding and stronger T-cell activation. In other words, improved immune recognition. This finding was backed up by an analysis of a large database of more than 17,000 British COVID-19 patients.

“This insight highlights a completely new aspect of the relationship between our bodies and viruses: the immune system doesn’t just respond to viruses, it also exerts a kind of genetically imprinted pressure on them that, over the long term, makes them easier to recognize,” explained Gergő Balogh, the study’s first author.

The phenomenon can be detected not only in coronavirus but in other viruses as well, and because of individual differences in HLA, it could open up new possibilities for personalized medicine. Mutation patterns created by APOBEC activity may help predict, even in the early stages of an outbreak, which new protein variants are likely to emerge in a virus. This kind of knowledge could be crucial for vaccine development and for designing personalized therapies.

The research was led by Máté Manczinger and Gergő Balogh with professional support from academicians Csaba Pál and Balázs Papp, while the experimental work was supervised by Gábor Szebeni.