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Structural Fluidity of the Human Immunodeficiency Virus Rev Response Element

Basic Research Laboratory, National Cancer Institute, Frederick, MD 21701, USA
Author to whom correspondence should be addressed.
Current address: Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20933, USA.
Viruses 2020, 12(1), 86;
Received: 3 December 2019 / Revised: 7 January 2020 / Accepted: 9 January 2020 / Published: 11 January 2020
(This article belongs to the Special Issue Antiviral Agents)
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. View Full-Text
Keywords: HIV; Rev response element; chemical footprinting; SHAPE; drug discovery; branched peptides HIV; Rev response element; chemical footprinting; SHAPE; drug discovery; branched peptides
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Sherpa, C.; Grice, S.F.J.L. Structural Fluidity of the Human Immunodeficiency Virus Rev Response Element. Viruses 2020, 12, 86.

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