tRNA modifications in viral replication.

tRNA modifications are key players in post-transcriptional gene expression regulation under external and cellular stresses. Viral infection is a common external stress that hijacks cellular processes for replication. Host cell tRNA pools and modification profiles are often reshaped during viral infection, eliciting both pro- and anti-viral effects. Changes in the host tRNA modifications, particularly in the anticodon sequence, have the capability to reprogram host and viral proteomes. For example, anticodon loop modifications contribute to programmed ribosomal frameshifting essential for producing certain viral proteins. However, the roles of tRNA modifications are not limited to translation during viral infection. Retroviruses use select host cell tRNAs as reverse transcription primers, and modifications modulate steps in reverse transcription. Furthermore, some non-primer modified tRNAs are selectively packaged into virion particles, though their functions remain unknown. Virally encoded tRNAs harbor modifications that expand the anticodon pool, as host tRNAs are depleted. Expression and activity of several tRNA-modifying enzymes are regulated upon viral infection, the functional implications of which remain to be elucidated. tRNA modifications are involved in anti-viral defense, particularly in tRNA cleavage at the anticodon loop following viral infection, leading to tRNA-derived fragments. While the tRNA modification landscape is likely significantly altered following most viral infections, current evidence is limited to a few specific examples. A global tRNAome analysis during viral infection will shed light on the regulation of these and other processes. Emerging technologies, including advances in direct tRNA sequencing and modification detection via mass spectrometry, are making this possible.