Rev (HIV)

The unknown protein functioned by removing repression of regulatory sequences and was named Art (anti-repression transactivator).

The arginine-rich motif (ARM) is located between amino acids 38–49 of the rev gene[6] and forms an alpha-helical secondary structure.

[7] The ARM is a highly specific sequence which allows for the multimerization of Rev proteins, prior to RNA binding.

[9] The alpha-helical secondary structure specifically can be considered a helix-loop-helix motif, which allows the REV protein to stably bind to the RRE RNA to form the ribonucleoprotein complex.

[14] Binding of Rev to viral RNAs containing the RRE allows for mRNA export out of the nucleus and into the cytoplasm by a mechanism different than that of cellular mRNAs.

However, Rev is needed to export incompletely spliced mRNAs in order to produce the viral structural proteins.

[citation needed] The rev response element (RRE) is a 240 base-pair sequence located in the second intron of the HIV-1 genome, immediately downstream of the env gene.

Within this purine-rich stem-loop, IIB, are non-canonical base pairs that form as a result of the mRNA stem loop-secondary structure.

Upon disassembly, Rev's NES forms a new complex with CRM1 (exportin-1) and Ran-GTP at the RRE sequence within incompletely spliced transcripts.

Rev-mediated export from the nucleus increases cytoplasmic levels of the structural mRNAs (gag, pol, and env).

Since Rev is continuously shuttled between the nucleus and cytoplasm, small amounts of the protein are able to impact many mRNA transcripts.

Maintenance of the proper balance between early and late viral gene quantities leads to an overall increase in virion production.

[citation needed] Leptomycin B (LMB) binds to CRM1 which prevents the formation of the complex required for export(CRM1/NES/RanGTP/RRE) and ultimately reduces the production of incompletely spliced RNAs.

Neomycin B, diphenylfuran cation, and proflavine are small molecules that can prevent Rev from binding to the RRE sequence.

[34][35][36] If Rev is incapable of binding to the RRE on the pre-mRNA, the RNA will not be exported to the cytoplasm, also resulting in lack of necessary structural proteins.

The secondary structure of the IIB binding site shows non-canonical base pairs G47 (magenta)-A73 (orange) and G48-G71 (magenta). Bulging, non-paired uridine nucleotide points outward from the secondary helix (colored red). The mRNA forms a stem-loop like structure with intricate folding (PDB 4PMI).
Shown are residues Arg35 and Arg39 (colored by element with IUPAC standards) that make specific contacts with residues uracil 66 (red), guanine 67, and guanine 70 (magenta) during RNA binding (PDB 4PMI).
Shown are residues N40 and R44 (colored by element with IUPAC standards) making specific contacts with residues uracil 45 (red), guanine 46 (magenta), guanine 47 (magenta), and adenine 73 (orange) (PDB 4PMI).