Virus-driven tRNA competition universally represses host genes with similar codon usage

Viral infection induces tRNA competition between viral and host genes, often repressing host translation. However, how endogenous genes are affected by this competition remains unclear. Three possible hypotheses are considered: abundant-tRNA shortage, rare-tRNA shortage, and viral similarity repression. Pan-virus Ribo-seq data show that endogenous genes with codon usage bias (CUB) matching host tRNA supply or viral CUB are strongly repressed, due to a positive correlation between endogenous CUB-tRNA mismatch and endogenous-viral CUB difference, supporting the abundant-tRNA shortage and viral similarity repression hypotheses. In E. coli experiments with synonymous gentamicin resistance proteins, this positive correlation supports abundant-tRNA shortage, while a non-positive correlation supports rare-tRNA shortage, and both positive and non-positive correlation types support viral similarity repression. Finally, analysis of human virus genomes reveals this positive correlation for most viruses, but a non-positive correlation in a few, reflecting diverse virus-host interaction strategies. These findings establish viral similarity repression as a universal principle, uncovering previously unrecognized complexity in virus-host coevolution.