Sensing nucleotide composition in virus RNA

Nucleotide composition plays a crucial role in the structure, function and recognition of RNA molecules. During infection, virus RNA is exposed to multiple endogenous proteins that detect local or global compositional biases and interfere with virus replication. Recent advancements in RNA:protein mapping technologies have enabled the identification of general RNA-binding preferences in the human proteome at basal level and in the context of virus infection. In this review, we explore how cellular proteins recognise nucleotide composition in virus RNA and the impact these interactions have on virus replication. Protein-binding G-rich and C-rich sequences are common examples of how host factors detect and limit infection, and, in contrast, viruses may have evolved to purge their genomes from such motifs. We also give examples of how human RNA-binding proteins inhibit virus replication, not only by destabilising virus RNA, but also by interfering with viral protein translation and genome encapsidation. Understanding the interplay between cellular proteins and virus RNA composition can provide insights into host–virus interactions and uncover potential targets for antiviral strategies.