The evolutionary dynamics between viral mimics and host proteins

Abstract Viral proteins interact with host proteins to hijack cellular pathways important for viral replication. Viral mimics are proteins whose structural similarity to host-mimicked proteins allows them to interact with mutual host targets. This mimicry poses a challenge for the host—how to avoid mimics without compromising essential interactions with host-mimicked proteins. Despite the prevalence of mimicry, the evolutionary dynamics between host and viral mimics remain largely unknown. We address this by integrating structural modeling, host–virus interaction networks, and comprehensive evolutionary analyses of host and viral proteins. We show that host proteins targeted by mimics and host-mimicked proteins are highly conserved, and that this is related to functional constraints imposed on host proteins. Host interface residues that interact with both mimics and host-mimicked proteins evolve slowly, while residues that exclusively interact with mimics evolve significantly faster. Surprisingly, viral mimics do not evolve rapidly, instead displaying complex evolutionary patterns. Our analysis reveals host’s limited capacity to escape mimicry and viral evolution to exploit this, and highlights how constraints lead to unexpectedly slow evolution of host–virus interaction networks.