April 2026: Hagai: Viruses exploit critical weak points in human cells

A new study led by Prof. Tzachi Hagai, Edmond J. Safra affiliate (Life Sciences), together with graduate students from his lab and researchers from University of Milan, reveals that viruses such as herpesviruses and poxviruses do not engage in a continuous evolutionary "arms race" with the human immune system. Instead, they exploit the cell’s most essential and evolutionarily conserved components - proteins so critical to cellular function that mutations in them would be lethal - limiting the host’s ability to evolve resistance without compromising its own survival.

Published in Molecular Systems Biology, the research shows that many viruses use molecular mimicry, producing viral proteins that structurally imitate key human proteins or short functional motifs. This allows viruses to integrate seamlessly into cellular interaction networks and hijack vital processes. Because these targeted human proteins are indispensable and highly conserved, the host cannot easily evolve to avoid the viral attack.

The study examined five large DNA viruses infecting humans, including several herpesviruses and vaccinia virus, a close relative of smallpox. Using AI-based protein structure prediction (AlphaFold), protein-protein interaction mapping, and evolutionary analysis across primate species, the researchers found that protein interfaces involved in viral mimicry are among the most evolutionarily stable in the human genome. These findings challenge the conventional view of virus-host evolution as a rapid arms race and instead highlight deep functional constraints that viruses strategically exploit.

The insights gained from this study may advance our understanding of viral pathogenicity, the range of hosts they can infect, and cross-species infection, and could inform future therapeutic strategies targeting conserved virus-host interaction interfaces.