Rev Protein, HIV-1 group M subtype C (GST)

Rev is a viral protein that escorts unspliced or incompletely spliced viral pre-mRNAs (late transcripts) out of the nucleus of infected cells. These pre-mRNAs carry a recognition sequence called Rev responsive element (RRE) located in the env gene, which is absent in fully spliced viral mRNAs (early transcripts). This function is essential because most viral proteins are translated from unspliced or partially spliced pre-mRNAs that cannot exit the nucleus via the pathway used by fully processed cellular mRNAs. Rev itself is translated from a fully spliced mRNA that readily exits the nucleus. Rev's nuclear localization signal (NLS) binds directly to KPNB1/Importin beta-1 without prior binding to KPNA1/Importin alpha-1. KPNB1 binds to the GDP-bound form of RAN (Ran-GDP) and targets Rev to the nucleus. In the nucleus, the conversion from Ran-GDP to Ran-GTP dissociates Rev from KPNB1, allowing Rev to bind to the RRE in viral pre-mRNAs. Rev multimerizes on the RRE through cooperative assembly, exposing its nuclear export signal (NES) on the surface. Rev can then form a complex with XPO1/CRM1 and Ran-GTP, facilitating nuclear export of the complex. Conversion from Ran-GTP to Ran-GDP mediates dissociation of the Rev/RRE/XPO1/RAN complex, enabling Rev to return to the nucleus for subsequent export cycles. Besides KPNB1, Rev also appears to interact with TNPO1/Transportin-1, RANBP5/IPO5, and IPO7/RANBP7 for nuclear import. The nucleoporin-like HRB/RIP is an essential cofactor that likely interacts indirectly with Rev to release HIV RNAs from the perinuclear region to the cytoplasm.