Muscolino, ElenaDíez Antón, Juana, 1962-2025-11-072025-11-072025Muscolino E, Diez J. Viral codon usage and the host transfer RNA. Annu Rev Virol. 2025 Sep;12(1):223-37. DOI: 10.1146/annurev-virology-092623-1054182327-056Xhttp://hdl.handle.net/10230/71810The expansion of viruses within cells requires efficient viral protein production. Counterintuitively, many viral genomes are enriched in suboptimal codons, which are typically associated with reduced protein outputs. Recent research using chikungunya virus (CHIKV) as a prototype model highlights the role of host transfer RNA (tRNA) modifications, collectively known as the tRNA epitranscriptome, in resolving this paradox. Upon infection, CHIKV triggers a DNA damage stress response that ultimately leads to changes in the tRNA epitranscriptome. These changes reprogram codon optimality, selectively enhancing the translation of specific suboptimal codons that are highly enriched in both host stress response genes and the viral genome. Hence, CHIKV codon usage optimally aligns with the tRNA modification landscape in infected cells. We propose that this interplay between viral codon usage, stress responses, and tRNA modifications is a shared strategy among viruses beyond CHIKV. Targeting this interplay may pave the way for the development of broad-spectrum antiviral therapies.application/pdfengCopyright © 2025 by the author(s). This work is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.info:eu-repo/semantics/article2025-11-07http://dx.doi.org/10.1146/annurev-virology-092623-105418DNA damage responseCodon optimalityCodon usagemcm5/mcm5s2tRNA epitranscriptomeVirusesinfo:eu-repo/semantics/openAccess