Structure of an RNA Aptamer that Can Inhibit HIV-1 by Blocking Rev-Cognate RNA (RRE) Binding and Rev-Rev Association

• Published in: Structure (London) Vol. 26; no. 9; pp. 1187 - 1195.e4
• Main Authors: Dearborn, Altaira D., Eren, Elif, Watts, Norman R., Palmer, Ira W., Kaufman, Joshua D., Steven, Alasdair C., Wingfield, Paul T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 04.09.2018; Elsevier
• Subjects: Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; aptamer; Aptamers, Nucleotide - chemistry; Aptamers, Nucleotide - pharmacology; Arginine - metabolism; assembly; Binding Sites; Crystallography, X-Ray; HIV-1; HIV-1 - drug effects; HIV-1 - metabolism; HIV-1 - physiology; inhibitor; Models, Molecular; Protein Binding - drug effects; Response Elements; Rev; rev Gene Products, Human Immunodeficiency Virus - antagonists & inhibitors; rev Gene Products, Human Immunodeficiency Virus - chemistry; rev Gene Products, Human Immunodeficiency Virus - genetics; Virus Replication - drug effects; HIV-1; assembly; Rev; inhibitor; aptamer
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2018.06.001

HIV-1 Rev protein mediates nuclear export of unspliced and partially spliced viral RNAs for production of viral genomes and structural proteins. Rev assembles on a 351-nt Rev response element (RRE) within viral transcripts and recruits host export machinery. Small (<40-nt) RNA aptamers that compete with the RRE for Rev binding inhibit HIV-1 viral replication. We determined the X-ray crystal structure of a potential anti-HIV-1 aptamer that binds Rev with high affinity (Kd = 5.9 nM). The aptamer is structurally similar to the RRE high-affinity site but forms additional contacts with Rev unique to its sequence. Exposed bases of the aptamer interleave with the guanidinium groups of two arginines of Rev, forming stacking interactions and hydrogen bonds. The aptamer also obstructs an oligomerization interface of Rev, blocking Rev self-assembly. We propose that this aptamer can inhibit HIV-1 replication by interfering with Rev-RRE, Rev-Rev, and possibly Rev-host protein interactions. [Display omitted] •X-ray crystal structure of potential anti-HIV-1 RNA aptamer•The aptamer binds to the arginine-rich motif of Rev•The aptamer blocks Rev self-assembly With age, people living with HIV-1 accrue co-morbidities that may affect anti-retroviral drug tolerance. Also, as anti-retroviral drugs are used, resistant viral strains enter circulation, making the development of additional anti-retroviral drugs desirable. We have determined the structure of a potential RNA-based HIV-1 inhibitor, bound to its target: HIV-1 Rev.