The HIV-1 rev trans-activator acts through a structured target sequence to activate nuclear export of unspliced viral mRNA

Abstract

Human immunodeficiency virus type 1 (HIV-1) replication requires the expression of two classes of viral mRNA. The early class of HIV-1 transcripts is fully spliced and encodes viral regulatory gene products. The functional expression of one of these nuclear regulatory proteins, termed Rev (formerly Art or Trs), induces the cytoplasmic expression of the incompletely spliced, late class of HIV-1 mRNAs that encode the viral structural proteins, including Gag and Env. Here, we provide evidence that this induction reflects the export from the cell nucleus to the cytoplasm of a pool of unspliced viral RNA constitutively expressed in the nucleus. The hypothesis that Rev acts on RNA transport, rather than splicing, is further supported by the observation that the cytoplasmic expression of a non-spliceable HIV-1 env gene sequence is also subject to Rev regulation. Here we show that this Rev response requires a specific target sequence which coincides with a complex RNA secondary structure present in the env gene. The response to Rev is fully maintained when this sequence is relocated to other exonic or intronic locations within env but is ablated by inversion. These results indicate that the HIV-1 rev gene product induces HIV-1 structural gene expression by activating the sequence-specific nuclear export of incompletely spliced HIV-1 RNA species.

Identification of an RNA element that confers post-transcriptional repression of connective tissue growth factor/hypertrophic chondrocyte specific 24 (ctgf/hcs24) gene: Similarities to retroviral RNA-protein interactions

“…The unspliced mRNA, which encodes viral structural and enzymatic protein precursors, is e ciently exported from the nucleus only when the viral Rex protein binds to the structured RNA segment entitled Rex-responsive element in the 3'-UTR. Of note, a similar mRNA export system is established in human immunode®-ciency virus type I (HIV-1) by the viral Rev protein and the Rev-responsive element (RRE) (Malim et al, 1989;Zapp and Green, 1989;Heaphy et al, 1991;Malim and Cullen, 1991;Fischer et al, 1994), which plays a key regulatory role in the viral life-cycle (Pomerantz et al, 1992). Interestingly, the Rev-RRE interactions were found to also promote the polysomal assembly and e cient translation of the RRE-containing mRNAs (Arrigo and Chen, 1991;D'Agostino et al, 1992).…”

AU-rich mRNA instability elements on human papillomavirus type 1 late mRNAs and c-fos mRNAs interact with the same cellular factors

“…This is consistent with our earlier results which demonstrated that the human immunode®ency type 1 (HIV-1) Rev/RRE regulatory axis could overcome the inhibitory e ect of the h1ARE . The HIV-1 Rev protein binds to its target RNA element in the nucleus and acts by promoting export of nuclear mRNAs (Emerman et al, 1989;Felber et al, 1989;HammarskjoÈ ld et al, 1989;Malim et al, 1989) through an alternative, productive route (Bogerd et al, 1995;Fisher et al, 1995;Fritz et al, 1995), thereby presumably preventing the h1ARE from interacting with nuclear proteins that mediate inhibition as the mRNA enters the cytoplasm. Recent reports have described the identi®cation of an RNaseE like activity in mammalian cells and have shown that partially puri®ed mammalian RNaseE cleaves AUUUA containing RNAs in vitro (Wennborg et al, 1995).…”

Mechanisms controlling titer and expression of bidirectional lentiviral and gammaretroviral vectors

“…Interestingly, strongly deaminized dsRNA will be retained within the nucleus unless additional export systems, such as the human immunodeficiency virus-1 (HIV-1)-derived Rev/Rev responsive element (RRE), are used. 24 Rev/RRE is normally responsible for the export of incompletely spliced HIV RNA 25 by hijacking the cellular Crm-1-dependent protein export machinery. 26 Rev also increases RNA stability and translation.…”