Lessons Learned and Yet-to-Be Learned on the Importance of RNA Structure in SARS-CoV-2 Replication

SARS-CoV-2, the etiological agent responsible for the COVID-19 pandemic, is a member of the virus family Coronaviridae, known for relatively extensive (~30-kb) RNA genomes that not only encode for numerous proteins but are also capable of forming elaborate structures. As highlighted in this review, these structures perform critical functions in various steps of the viral life cycle, ultimately impacting pathogenesis and transmissibility. We examine these elements in the context of coronavirus evolutionary history and future directions for curbing the spread of SARS-CoV-2 and other potential human coronaviruses. While we focus on structures supported by a variety of biochemical, biophysical, and/or computational methods, we also touch here on recent evidence for novel structures in both protein-coding and noncoding regions of the genome, including an assessment of the potential role for RNA structure in the controversial finding of SARS-CoV-2 integration in “long COVID” patients. This review aims to serve as a consolidation of previous works on coronavirus and more recent investigation of SARS-CoV-2, emphasizing the need for improved understanding of the role of RNA structure in the evolution and adaptation of these human viruses.