Viral genomes evolve to maximise the potential to overcome the defence mechanisms of the host they are infecting. The genomes of RNA viruses, such as the human immunodeficiency virus (HIV) and coronaviruses, are single stranded, and can fold upon themselves to form complex secondary structures. Riboswitches are highly structured RNA segments binding to small-molecule ligands. They have recently been increasingly understood to play a crucial role in the infectiousness and severity of viral diseases. The latest advances in the field of RNA therapy already allow for the manufacturing of small molecules capable of disrupting specific RNA secondary structures. Soon virus-specific RNA switches could be re-coded to express products able to block viral replication. As such, the RNA structurome constitutes an exciting target for new drug discovery.
However, the structurome, while once considered a fixed feature, is now understood to be a very complex dynamical system, with multiple structural conformations often available to the RNA. Riboswitches are thought to make use of this structural heterogeneity to regulate key genes expression. To identify and exploit riboswitches, it is therefore essential to draw a full picture of their structural landscape. Thanks to the emergence of new experimental technologies, we were able to develop a software package, DREEM, to precisely identify and characterise RNA structural heterogeneity. Using DREEM, we were able to identify a potential riboswitch in HIV1,2, which uses two alternative structures to regulate the translation of Tat, a protein which controls viral gene expression.