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

Viral infection triggers a competition for transfer RNAs between viral and host endogenous genes, often leading to the repression of endogenous gene translation. However, how endogenous genes are affected by this competition remains unclear. Three possible answers are considered: the abundant-tRNA shortage hypothesis, the rare-tRNA shortage hypothesis, and the viral similarity repression hypothesis. Using pan-virus Ribo-seq data, it is found that endogenous genes whose codon usage bias (CUB) matches 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 the viral similarity repression hypotheses. In E. coli manipulative experiments with synonymous gentamicin resistance proteins, this positive correlation supports the abundant-tRNA shortage hypothesis, a non-positive correlation supports the rare-tRNA shortage hypothesis, and both positive and non-positive correlation support the viral similarity repression hypothesis. Finally, analysis of human virus genomes reveals this positive correlation for most viruses, but a non-positive correlation is found in a few, reflecting the diversity of virus-host interaction strategies. These findings establish viral similarity repression as a universal principle, a previously unrecognized complexity in the diverse coevolution of virus and host.