**Chringma Sherpa** † **and Stuart F. J. Le Grice \***

Basic Research Laboratory, National Cancer Institute, Frederick, MD 21701, USA; chringma@gmail.com **\*** Correspondence: legrices@mail.nih.gov; Tel.: +1-(301)-846-5256; Fax: +1-(301)-846-6013

† 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.

Received: 3 December 2019; Accepted: 9 January 2020; Published: 11 January 2020

**Abstract:** 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.

**Keywords:** HIV; Rev response element; chemical footprinting; SHAPE; drug discovery; branched peptides
