Curr Opin Virol. 2026 Apr 08. pii: S1879-6257(26)00019-2. [Epub ahead of print]76
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Orthoflaviviruses, a genus of RNA viruses transmitted primarily by arthropods, exhibit remarkable adaptability, infecting a broad range of hosts, from insects to vertebrates, despite their compact ∼11-kilobase genome. To maximize their functional repertoire and modulate host interactions, they employ a variety of canonical and noncanonical expression mechanisms. Here, we discuss how orthoflaviviruses utilize noncoding RNAs, including subgenomic flavivirus RNAs and viral microRNAs, as well as unconventional translational strategies, such as upstream open reading frames and programmed ribosomal frameshifting, to enhance viral replication, evade immune responses, and adapt to diverse hosts. These noncanonical genome optimization strategies highlight the evolutionary plasticity of orthoflaviviruses, enabling them to manipulate the cellular machinery of phylogenetically distant hosts. Understanding these mechanisms not only advances our knowledge of the biology of these emerging and re-emerging viruses but also provides insights for developing antiviral therapies and vaccine strategies.