tRNA Modifications: A Tale of Two Viruses – SARS-CoV-2 and ZIKV

tRNA modifications are crucial for efficient protein synthesis, impacting codon recognition, tRNA stability, and translation rates. RNA viruses hijack the host’s translational machinery, including the pool of modified tRNA, to translate their own genomes. However, the mismatch between viral and host codon usage can lead to limited availability of specific tRNA leading to ribosome stalling, and posing a significant challenge for efficient protein translation. While some viruses address this challenge through codon optimization, we show here that SARS-CoV-2 (Coronavirus) and Zika virus (ZIKV; Flavivirus) adopt a different approach, manipulating the host tRNA epitranscriptome. Analysis of codon bias indices confirmed substantial divergence between viral and host codon usage, revealing a strong preference in viral genes for codons decoded by tRNAs requiring U34 wobble modification. Monitoring tRNA modification dynamics in infected cells showed that both SARS-CoV2 and ZIKV enhance U34 tRNA modifications during infection. Strikingly, impairing U34 tRNAs profoundly impacted viral replication underscoring the strict reliance of SARS-CoV-2 and ZIKV on manipulating the host tRNA epitranscriptome to support efficient translation of their genome.