Regulator of Virion

Rev is a transactivating protein that is essential to the regulation of HIV-1 protein expression. A nuclear localization signal is encoded in the rev gene, which allows the Rev protein to be localized to the nucleus, where it is involved in the export of unspliced and incompletely spliced mRNAs. In the absence of Rev, mRNAs of the HIV-1 late (structural) genes are retained in the nucleus, preventing their translation.

A novel protein was found to be involved in the translation of gag and env mRNA. The unknown protein functioned by removing repression of regulatory sequences and was named Art (anti-repression transactivator). Later studies suggested that the protein was involved in regulation of the RNA splicing mechanism. Therefore, the name of the protein was modified from Art to Trs (transregulator of splicing). The most recent studies have shown that the protein has multiple functions in the regulation of HIV-1 proteins, and its name has been changed to Rev (regulator of expression of virion proteins), which more generally describes its function.

Rev is a 13-kDa protein that is composed of 116 amino acids. Rev’s sequence contains two specific domains which contribute to its nuclear import and export. The protein typically performs its function as a tetramer.

The N-terminal region of Rev contains an arginine-rich sequence. The arginine-rich motif (ARM) is located between amino acids 38-49 of the rev gene and forms an alpha-helical secondary structure. The ARM is a highly specific sequence which allows for the multimerization of Rev proteins, prior to RNA binding. A single base substitution alters Rev’s ability to form a tetramer. The arginine-rich domain of Rev interacts with the rev-binding element (RBE), which is part of the HIV Rev response element (RRE) located in an intron downstream of the env gene. The domain also contains a nuclear localization signal.

Rev’s nuclear export signal is located in residues 71-82 of the C-terminal region and is leucine-rich. 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.

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