HIV Rev response element

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.

The HIV-1 genome contains a single promoter and uses multiple reading frames and alternative splicing to encode 15 proteins from a single pre-mRNA species.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 early phase of the viral life cycle, this pre-RNA is completely spliced to RRE-free, 2 kb messages. These smaller messages are then transported from the nucleus to the cytoplasm via standard mRNA nuclear export pathways (see Figure). One of these small, 2kb messages encodes the HIV-1 Rev protein which is imported into the nucleus via its nuclear localization sequence. This phase of the virus life cycle is both Rev and RRE independent.

The late phase of the viral life cycle is characterized by the expression of viral proteins that are encoded on the long, unspliced (9kb) or partially spliced (4 kb) messages containing the RRE. Because of their retention and splicing signals, these intron-containing RNAs are initially retained in the nucleus for splicing/degradation. However, after a sufficient level of Rev has been produced by the 2 kb messages, these longer messages can be exported to the cytoplasm via a Rev dependent export pathway. Nuclear export of these RNAs is achieved by a specific, co-operative assembly of multiple Rev molecules on the RRE. Assembly of this Rev-RRE complex is followed by the recruitment of a human protein complex containing the proteins exportin-1 (XPO1/CRM1) and Ran-GTP. Rev recruits this export machinery via a nuclear export sequence (NES) present in Rev. This Rev-RRE-Xpo1/RanGTP complex is then transported to the cytoplasm. In the cytoplasm, these messages are translated to produce all the remaining viral proteins or packaged as genomes for newly budding virions (see Figure).

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