Disease relevance of rev

• This genetic complementation by rex is adequate for the rescue of a replication-defective rev mutant of HIV-1 [1].
• Each virus also produces a second trans-acting protein that induces the expression of the unspliced messenger RNAs encoding the viral structural proteins (rev in HIV and rex in HTLV) [1].
• Here we show that the rex protein of HTLV-I can functionally replace the rev protein of HIV-1 in transient expression assays [1].
• This unexpected shared function between the structurally distinct rex and rev proteins emphasizes the importance of this highly conserved pathway for the regulation of human retrovirus gene expression [1].
• This third-generation lentivirus vector uses only a fractional set of HIV genes: gag, pol, and rev [2].

Psychiatry related information on rev

• This conclusion, taken together with the observed permissiveness of a variety of eukaryotic cell types for Rev function, suggests that the target for the activation domain of Rev is likely to be a highly conserved cellular protein(s) intrinsic to nuclear mRNA transport or splicing [3].

High impact information on rev

• Thus, the Rev activation domain constitutes a nuclear export signal that redirects RRE-containing viral RNAs to a non-mRNA export pathway [4].
• HIV-1 Rev protein directs nuclear export of pre-mRNAs and mRNAs containing its binding site, the Rev response element (RRE) [4].
• BSA-R inhibited Rev-mediated nuclear RNA export, whereas a mutant activation domain peptide conjugate did not [4].
• The results suggest that Rev directly promotes the cytoplasmic transport of suitable transcripts by targeting them to the nuclear pore [5].
• A 17 amino acid peptide containing the arginine-rich region of the HIV Rev protein binds specifically to Rev response element (RRE) RNA [6].

Chemical compound and disease context of rev

• Rev-dependent association of the intron-containing HIV-1 gag mRNA with the nuclear actin bundles and the inhibition of its nucleocytoplasmic transport by latrunculin-B [7].
• BACKGROUND: The HIV-1 Rev protein mediates nuclear export of unspliced and partially spliced viral RNA through interaction with the Rev response element (RRE) by means of an arginine rich motif that is similar to the one found in Tat [8].
• The detrimental effect of a strong 3' splice site on the amount of Rev-dependent intron-containing HIV-1 glycoprotein coding (env) mRNA is not compensatable by weakening the strength of the upstream 5' splice site [9].
• Human immunodeficiency virus type 1 (HIV-1) Rev-mediated nuclear export of viral RNAs involves the interaction of its leucine-rich nuclear export sequence (NES) with nuclear cofactors [10].
• Interaction of eukaryotic initiation factor 5A with the human immunodeficiency virus type 1 Rev response element RNA and U6 snRNA requires deoxyhypusine or hypusine modification [11].

Biological context of rev

• The SIV packaging plasmid was also modified with regard to the requirement for RRE and rev [12].
• Most detailed analyses of the human immunodeficiency virus type 1 (HIV-1) rev gene product have relied on transfection of subgenomic env constructs into cells in which amplification of the transfected DNA occurs [13].
• Despite encoding full-length open reading frames for gp120 and gp41 and the second coding exon of tat and rev, each chimera was replication defective [14].
• Similarly, mutagenesis of rev codon 78 of NL4-3 from Leu to Ile partially attenuated this virus [14].
• In addition to the structural genes, HIV contains two regulatory genes, tat and rev, that are essential for HIV replication, and four accessory genes that encode critical virulence factors [2].

Anatomical context of rev

• None of the transgenic mice that expressed vif, tat, rev, or vpu in podocytes, even with the FVB/N genetic background, developed podocyte injury [15].
• Diminished rev-mediated stimulation of human immunodeficiency virus type 1 protein synthesis is a hallmark of human astrocytes [16].
• Nef, Rev, and Tat putative B- and T-cell epitopes were clearly mapped by using peptides derived from the regulatory proteins and were similar to those which are detected in human immunodeficiency virus infection [17].
• To this end, we compared the trans activation capacity and intracellular distribution of Rev in four astrocytoma cell lines previously shown to be infectible by HIV-1 and in primary human fetal astrocytes from different sources with Rev-permissive nonglial control cell lines [16].
• This suggests that Rev is necessary and probably also sufficient for the accumulation of incompletely spliced HIV RNAs at the nuclear pores while CRM1 is needed for translocation across the nuclear pore complex [18].

Associations of rev with chemical compounds

• This correlated with increased usage of the four most 3' branch points, which include those within the rev 3' splice site AG dinucleotides [19].
• Binding of the Rev arginine rich motif to the RRE was reduced in the presence of wild-type PRMT6, whereas mutant PRMT6 did not exert this negative effect [8].
• In addition, diminished interactions between viral RNA and mutant Rev proteins were observed, due to the introduction of single arginine to lysine substitutions in the Rev arginine rich motif [8].
• This model system can be used to evaluate the efficacy of anti-HIV-1 vaccines directed at the envelope glycoproteins, anti-HIV-1 envelope glycoprotein antiserum or monoclonal antibodies, and anti-HIV-1 drugs designed to inhibit the tat, rev, or env functions [20].
• In marked contrast to this, ribozyme cleaved RNA accumulated almost exclusively (n/c ratio of 28) in the nucleus in the presence of Rev. Actinomycin D time course analysis suggested that the low levels of the cytoplasmic ribozyme-cleaved RNAs in both the presence and absence of Rev were due to serve export deficiency of ribozyme-cleaved RNA [21].

Physical interactions of rev

• 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 [22].
• Here, we confirm that fusion of Tat to the RNA-binding domain of the HIV-1 Rev protein permits the efficient activation of an HIV-1 long terminal repeat (LTR) promoter in which critical TAR sequences have been replaced by RNA sequences derived from the HIV-1 Rev response element (RRE) [23].

Regulatory relationships of rev

• Therefore, Rev down regulates its own expression and the expression of Tat and Nef [24].
• We examined whether the codon bias observed in the vpu and vif genes relative to highly expressed human genes contributes to the Rev dependence and low expression level outside the context of the viral genome [25].
• Similarly, cells transduced with LrevSN were able to rescue a rev- HIV-1 provirus, indicating the presence of a functional Rev. We also used LnefSN to obtain clones of cells expressing Nef [26].
• In the nuclear expression system, Rev enhanced env mRNA transport by about 1.6-fold, while translation of this mRNA was increased more than a 100-fold [27].

Other interactions of rev

• Tat and rev appear to be prototypes of novel eukaryotic regulatory proteins [28].
• In support of this possibility, mutations at rev 3' splice site A4b AG dinucleotide dramatically increased splicing of the env/nef 3' splice site A5 [19].
• Single point mutation of M1 within an infectious molecular clone is detrimental for HIV-1 exon 2 recognition without affecting Rev-dependent vif expression [9].

Analytical, diagnostic and therapeutic context of rev

• Trans-dominant mutants of human immunodeficiency virus type 1 (HIV-1) Tat and Rev are attractive candidates for use in gene therapy in the treatment of HIV-1 infections because both are essential for viral replication [29].
• Site-directed mutagenesis of codon 78 in the Rev activation domain (from a hitherto unique Ile to the subtype B consensus Leu) partially restored infectivity for two of three chimeras tested [14].
• In all astrocytic cell cultures, the Rev response was reduced to about 10% of that of Rev-permissive control cells [16].
• RESULTS: Fluorescence in situ hybridization and immunocytochemistry demonstrated that gag mRNA, Rev, and its NES receptor, CRM1, and RanGTPase formed nuclear tracks which were congruent with underlying beta-actin bundles [7].
• Here, we evaluated whether vaccination with Tat or Tat and Rev could significantly reduce viral load in nonhuman primates [30].

References