Researchers at Goethe University Frankfurt have discovered that RNA viruses exploit programmed ribosomal frameshifting not only to encode their proteins, but also to manipulate the cells they infect. During frameshifting, ribosomes – the molecular machines responsible for protein production – pause at structured regions of viral RNA. The new study, published in Cell, shows that these pauses can cause ribosomes to collide, creating molecular “traffic jams” that activate the cellular stress sensor GCN2. This stress response reduces host protein production and creates conditions that favor viral replication.

The researchers identified key components of this pathway and showed that the same principle operates in SARS-CoV-2, HIV-1 and West Nile virus. “Our findings change the way we think about ribosomal frameshifting,” says Audrey Xavier, one of the first authors and postdoctoral researcher at IBC2. “It is not simply a trick viruses use to squeeze more information into small genomes. Viruses exploit the resulting ribosomal stress as a signal to reprogram the host cell in their favor.”

The findings reveal a shared vulnerability of several medically important RNA viruses and suggest that components of this stress pathway could provide starting points for future broad-spectrum antiviral strategies. This is particularly relevant for emerging and mosquito-borne viruses such as West Nile virus, which continues to spread across Europe and can cause severe and sometimes fatal infections. There is currently no specific antiviral treatment for West Nile virus infection.

“We therefore need to invest in understanding potentially dangerous pathogens before they cause the next major outbreak, rather than waiting until a crisis has begun,” says IBC2 Director Ivan Đikić, senior author of the study. “Our work illustrates the value of identifying fundamental mechanisms shared across very different viruses. Such common vulnerabilities may ultimately help us develop broad-spectrum antiviral strategies and better prepare for future viral threats.”