The HIV-1 Rev response element (RRE) is a highly structured, ~350 nucleotide RNA segment present in the Env coding region of unspliced and partially spliced viral mRNAs.
In the presence of the HIV-1 accessory protein Rev, HIV-1 mRNAs that contain the RRE can be exported from the nucleus to the cytoplasm for downstream events such as translation and virion packaging.
[3] Transcription from an integrated HIV-1 provirus generates a single 9 kilobase (kb) pre-mRNA containing multiple splice sites and nuclear retention signals.
In the cytoplasm, these messages are translated to produce all the remaining viral proteins or packaged as genomes for newly budding virions (see Figure).
Computational predictions, later verified by chemical and enzymatic probing, indicate that RRE contains multiple stem loops and bulges (see Figure).
[5] This structure reveals an RNA A-form major groove widened by purine-purine base pairs at the purine-rich bulge to accommodate the a-helical Rev-ARM.
[6] Although Stems IIB and IA can bind Rev in isolation, a full-length RRE (at least ~250 nt) is required for viral function.
Multiple molecules of Rev bind to the full RRE in a specific and co-operative manner through a combination of Rev-RNA and Rev-Rev interactions.
[9] In a sense, the RRE acts as a scaffolding platform onto which a specific and co-operative complex of Revs (and eventually cellular export machinery) assembles.
[18] Various RNA cleavage methods and small molecule screens[19] have been implemented in an effort to design antiviral drugs to treat HIV infection by metallopeptide structures.
RRE Location in the HIV-1 Genome.
RRE is located within the Env coding region of HIV-1.
HIV-1 RNA export.
In the early phase (top), transcribed viral RNAs (9kb) are spliced down to 2kb before export. One of these 2kb messages is translated to produce Rev which is then imported into the nucleus. In the late phase (bottom), Rev binds the RRE of newly transcribed RNAs before splicing and exports the unspliced (9kb) and partially spliced (4kb) messages to the cytoplasm. Translation of these messages produces late stage viral proteins. 9 kb messages can also serve as genomes for new virions.
RRE Secondary Structure.
Secondary Structure of the minimal functional RRE (~250 nt). The RRE contains several stem loops, the most well characterized being the high affinity binding site, IIB. IIB is necessary but not sufficient for RRE mediated export. Stem IA is a more recently identified, secondary binding site. The remaining binding sites on the RRE have not been characterized yet.
Rev-ARM/IIB structure.
(Left) Stem IIB RNA(red) A-‐form major groove cradling the Rev-‐ARM α-‐helix (blue). The Rev-ARM is a short peptide that represents the RNA binding domain of Rev. (Right) A rotated view showing the purine-‐purine base pairs (yellow) that widen the RNA major groove.
Jellyfish model of Rev/RRE assembly.
This is a schematic representation of how an export-competent Rev–RRE complex might form: Rev molecules assemble onto the RRE scaffold to form an oligomeric assembly. In the “jellyfish” model, the jellyfish head comprises Rev oligomers and RRE; the Rev–NESs form the "tentacles" that interact with Crm1 (shown in the space-filled model) making the complex ready for export.
