Structural Fluidity of the Human Immunodeficiency Virus Rev Response Element

• Published in: Viruses Vol. 12; no. 1; p. 86
• Main Authors: Sherpa, Chringma, Grice, Stuart F. J. Le
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 11.01.2020; MDPI
• Subjects: Binding sites; branched peptides; Cell culture; chemical footprinting; Cloning; Drug Discovery; evolution; Flexibility; Fluidity; genome; Genome, Viral; Genomes; High-Throughput Nucleotide Sequencing; High-throughput screening; high-throughput screening methods; HIV; HIV-1 - genetics; HIV-1 - physiology; Human immunodeficiency virus; Human immunodeficiency virus 1; Human immunodeficiency virus 2; Humans; Localization; Mutagenesis; Mutation; nucleocytoplasmic transport; patients; Protein structure; Proteins; regulatory sequences; Response Elements; rev Gene Products, Human Immunodeficiency Virus - chemistry; rev Gene Products, Human Immunodeficiency Virus - genetics; Rev protein; rev response element; Review; RNA; RNA viruses; RNA, Viral - genetics; screening; shape; therapeutics; topology; SHAPE; HIV; drug discovery; chemical footprinting; branched peptides; Rev response element
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v12010086

Nucleocytoplasmic transport of unspliced and partially spliced human immunodeficiency virus (HIV) RNA is mediated in part by the Rev response element (RRE), a ~350 nt cis-acting element located in the envelope coding region of the viral genome. Understanding the interaction of the RRE with the viral Rev protein, cellular co-factors, and its therapeutic potential has been the subject of almost three decades of structural studies, throughout which a recurring discussion theme has been RRE topology, i.e., whether it comprises 4 or 5 stem-loops (SLs) and whether this has biological significance. Moreover, while in vitro mutagenesis allows the construction of 4 SL and 5 SL RRE conformers and testing of their roles in cell culture, it has not been immediately clear if such findings can be translated to a clinical setting. Herein, we review several articles demonstrating remarkable flexibility of the HIV-1 and HIV-2 RREs following initial observations that HIV-1 resistance to trans-dominant Rev therapy was founded in structural rearrangement of its RRE. These observations can be extended not only to cell culture studies demonstrating a growth advantage for the 5 SL RRE conformer but also to evolution in RRE topology in patient isolates. Finally, RRE conformational flexibility provides a target for therapeutic intervention, and we describe high throughput screening approaches to exploit this property.