rev gene products


Summary: Trans-acting nuclear proteins whose functional expression are required for retroviral replication. Specifically, the rev gene products are required for processing and translation of the gag and env mRNAs, and thus rev regulates the expression of the viral structural proteins. rev can also regulate viral regulatory proteins. A cis-acting antirepression sequence (CAR) in env, also known as the rev-responsive element (RRE), is responsive to the rev gene product. rev is short for regulator of virion.

Top Publications

  1. Elfgang C, Rosorius O, Hofer L, Jaksche H, Hauber J, Bevec D. Evidence for specific nucleocytoplasmic transport pathways used by leucine-rich nuclear export signals. Proc Natl Acad Sci U S A. 1999;96:6229-34 pubmed
  2. Nappi F, Schneider R, Zolotukhin A, Smulevitch S, Michalowski D, Bear J, et al. Identification of a novel posttranscriptional regulatory element by using a rev- and RRE-mutated human immunodeficiency virus type 1 DNA proviral clone as a molecular trap. J Virol. 2001;75:4558-69 pubmed
    ..Taken together, our results identify a novel posttranscriptional control element that uses a conserved cellular export mechanism. ..
  3. Wodrich H, Bohne J, Gumz E, Welker R, Krausslich H. A new RNA element located in the coding region of a murine endogenous retrovirus can functionally replace the Rev/Rev-responsive element system in human immunodeficiency virus type 1 Gag expression. J Virol. 2001;75:10670-82 pubmed
    ..There was no overall homology between the IAPE and the CTE, but there was complete sequence identity between short putative single-stranded loops. Deletion of these loops from the IAPE severely reduced Rev-independent Gag expression. ..
  4. Dayton A. Within you, without you: HIV-1 Rev and RNA export. Retrovirology. 2004;1:35 pubmed
    ..This suggests the ubiquity of RNA helicases in RNA export from the nucleus, and has novel mechanistic implications. ..
  5. Bogerd H, Echarri A, Ross T, Cullen B. Inhibition of human immunodeficiency virus Rev and human T-cell leukemia virus Rex function, but not Mason-Pfizer monkey virus constitutive transport element activity, by a mutant human nucleoporin targeted to Crm1. J Virol. 1998;72:8627-35 pubmed
    ..In addition, these data identify a novel and highly potent inhibitor of leucine-rich NES-dependent nuclear export...
  6. Boris Lawrie K, Roberts T, Hull S. Retroviral RNA elements integrate components of post-transcriptional gene expression. Life Sci. 2001;69:2697-709 pubmed
    ..Further characterization of the cellular partners and their regulation will be an important step to full understanding of nuclear-cytoplasmic connections that hardwire post-transcriptional gene expression in eukaryotic cells. ..
  7. Stutz F, Izaurralde E, Mattaj I, Rosbash M. A role for nucleoporin FG repeat domains in export of human immunodeficiency virus type 1 Rev protein and RNA from the nucleus. Mol Cell Biol. 1996;16:7144-50 pubmed
    ..The results suggest that Rev and cellular mediators of RNA export can interact with multiple components of the nuclear pore complex during transport, analogous to the proposed mode of action of the nuclear protein import receptor. ..
  8. Szebeni A, Mehrotra B, Baumann A, Adam S, Wingfield P, Olson M. Nucleolar protein B23 stimulates nuclear import of the HIV-1 Rev protein and NLS-conjugated albumin. Biochemistry. 1997;36:3941-9 pubmed
  9. Marin O, Sarno S, Boschetti M, Pagano M, Meggio F, Ciminale V, et al. Unique features of HIV-1 Rev protein phosphorylation by protein kinase CK2 ('casein kinase-2'). FEBS Lett. 2000;481:63-7 pubmed

More Information


  1. D Agostino D, Felber B, Harrison J, Pavlakis G. The Rev protein of human immunodeficiency virus type 1 promotes polysomal association and translation of gag/pol and vpu/env mRNAs. Mol Cell Biol. 1992;12:1375-86 pubmed
    ..These findings indicate that the presence of Rev is required along the entire mRNA transport and utilization pathway for the stabilization, correct localization, and efficient translation of RRE-containing mRNAs. ..
  2. Zolotukhin A, Felber B. Nucleoporins nup98 and nup214 participate in nuclear export of human immunodeficiency virus type 1 Rev. J Virol. 1999;73:120-7 pubmed
    ..Taken together, the recruitment of Nup98 and Nup214 by Rev and the competitive inhibition exhibited by their NP domains demonstrate direct participation of Nup98 and Nup214 in the Rev-hCRM1-mediated export. ..
  3. Askjaer P, Jensen T, Nilsson J, Englmeier L, Kjems J. The specificity of the CRM1-Rev nuclear export signal interaction is mediated by RanGTP. J Biol Chem. 1998;273:33414-22 pubmed
    ..Our data are consistent with a model in which CRM1 is the nuclear export receptor for the Rev-RRE ribonucleoprotein complex and that RanGTP binds to a preformed Rev-CRM1 complex and specifies a functional interaction with the NES. ..
  4. Emerman M, Malim M. HIV-1 regulatory/accessory genes: keys to unraveling viral and host cell biology. Science. 1998;280:1880-4 pubmed
    ..Detailed analysis of the interplay between these viral proteins and normal cellular activities has provided new insights into central questions of virology and host cell biology. ..
  5. Henderson B, Percipalle P. Interactions between HIV Rev and nuclear import and export factors: the Rev nuclear localisation signal mediates specific binding to human importin-beta. J Mol Biol. 1997;274:693-707 pubmed
    ..The series of interactions we describe provide a novel pathway for the import of Rev across the nuclear pore complex, and a mechanism for its release into the nucleoplasm. ..
  6. Yi R, Bogerd H, Cullen B. Recruitment of the Crm1 nuclear export factor is sufficient to induce cytoplasmic expression of incompletely spliced human immunodeficiency virus mRNAs. J Virol. 2002;76:2036-42 pubmed
  7. Venkatesh L, Gettemeier T, Chinnadurai G. A nuclear kinesin-like protein interacts with and stimulates the activity of the leucine-rich nuclear export signal of the human immunodeficiency virus type 1 rev protein. J Virol. 2003;77:7236-43 pubmed
    ..Thus, REBP displays the characteristics expected of an authentic mediator of Rev NES function and may play a role in RRE RNA transport during HIV infection. ..
  8. Gallego J, Greatorex J, Zhang H, Yang B, Arunachalam S, Fang J, et al. Rev binds specifically to a purine loop in the SL1 region of the HIV-1 leader RNA. J Biol Chem. 2003;278:40385-91 pubmed
    ..HIV-1 appears to have a second Rev-binding site close to the major splice donor site that may have an additional role in the viral life cycle. ..
  9. Meggio F, D Agostino D, Ciminale V, Chieco Bianchi L, Pinna L. Phosphorylation of HIV-1 Rev protein: implication of protein kinase CK2 and pro-directed kinases. Biochem Biophys Res Commun. 1996;226:547-54 pubmed
    ..In contrast, a mutation (R14TV-->EED) which suppresses Rev activity dramatically enhances Rev phosphorylation either in vitro by CK2 or in vivo, suggesting that phosphorylation by CK2 could play a role in Rev down-regulation. ..
  10. Cochrane A, Perkins A, Rosen C. Identification of sequences important in the nucleolar localization of human immunodeficiency virus Rev: relevance of nucleolar localization to function. J Virol. 1990;64:881-5 pubmed
    ..These findings support a model whereby Rev-induced export of human immunodeficiency virus structural mRNAs from the nucleus to the cytoplasm is likely to involve nucleolar events. ..
  11. Lee J, Murphy S, Belshan M, Sparks W, Wannemuehler Y, Liu S, et al. Characterization of functional domains of equine infectious anemia virus Rev suggests a bipartite RNA-binding domain. J Virol. 2006;80:3844-52 pubmed
    ..These findings suggest that EIAV Rev utilizes a bipartite RNA-binding domain...
  12. Tabernero C, Zolotukhin A, Valentin A, Pavlakis G, Felber B. The posttranscriptional control element of the simian retrovirus type 1 forms an extensive RNA secondary structure necessary for its function. J Virol. 1996;70:5998-6011 pubmed
    ..These data further support our in vitro mutagenesis data and demonstrate the importance of the sequence and structure of the SRV-1 CTE for appropriate function. ..
  13. Sánchez Velar N, Udofia E, Yu Z, Zapp M. hRIP, a cellular cofactor for Rev function, promotes release of HIV RNAs from the perinuclear region. Genes Dev. 2004;18:23-34 pubmed
    ..Thus, hRIP is an essential cellular Rev cofactor, which acts at a previously unanticipated step in HIV-1 RNA export: movement of RNAs from the nuclear periphery to the cytoplasm. ..
  14. Surendran R, Herman P, Cheng Z, Daly T, Ching Lee J. HIV Rev self-assembly is linked to a molten-globule to compact structural transition. Biophys Chem. 2004;108:101-19 pubmed
    ..These spectroscopic and hydrodynamic results imply that monomeric Rev is in a molten globule state, which becomes more compact upon self-association. ..
  15. Meyer B, Malim M. The HIV-1 Rev trans-activator shuttles between the nucleus and the cytoplasm. Genes Dev. 1994;8:1538-47 pubmed
    ..In addition, these results also identify, for the first time, a peptide sequence that is important for nuclear export. ..
  16. Bogerd H, Fridell R, Madore S, Cullen B. Identification of a novel cellular cofactor for the Rev/Rex class of retroviral regulatory proteins. Cell. 1995;82:485-94 pubmed
    ..We conclude that Rab is the predicted activation domain-specific cofactor for the Rev/Rex class of RNA export factors. ..
  17. Havlin R, Blanco F, Tycko R. Constraints on protein structure in HIV-1 Rev and Rev-RNA supramolecular assemblies from two-dimensional solid state nuclear magnetic resonance. Biochemistry. 2007;46:3586-93 pubmed
    ..In addition, the 2D spectra suggest the presence of additional helix content at Ile and Val sites in the C-terminal half of Rev. ..
  18. Neumann M, Afonina E, Ceccherini Silberstein F, Schlicht S, Erfle V, Pavlakis G, et al. Nucleocytoplasmic transport in human astrocytes: decreased nuclear uptake of the HIV Rev shuttle protein. J Cell Sci. 2001;114:1717-29 pubmed
    ..Our studies suggest a model in which Rev is prevented from functioning efficiently in astrocytes by specific alterations of its nucleocytoplasmic trafficking properties. ..
  19. Lucke S, Grunwald T, Uberla K. Reduced mobilization of Rev-responsive element-deficient lentiviral vectors. J Virol. 2005;79:9359-62 pubmed
    ..Thus, RRE-deficient lentiviral vectors provide a novel approach to reduce the risk of vector mobilization. ..
  20. Modem S, Badri K, Holland T, Reddy T. Sam68 is absolutely required for Rev function and HIV-1 production. Nucleic Acids Res. 2005;33:873-9 pubmed
    ..Taken together, these results suggest that Sam68 is involved in Rev-mediated RNA export and is absolutely required for HIV production. ..
  21. Daelemans D, Costes S, Cho E, Erwin Cohen R, Lockett S, Pavlakis G. In vivo HIV-1 Rev multimerization in the nucleolus and cytoplasm identified by fluorescence resonance energy transfer. J Biol Chem. 2004;279:50167-75 pubmed
    ..Our results show that Rev multimerizes in the nucleolus of living cells, suggesting an important role of the nucleolus in nucleocytoplasmic transport. ..
  22. Zolotukhin A, Michalowski D, Bear J, Smulevitch S, Traish A, Peng R, et al. PSF acts through the human immunodeficiency virus type 1 mRNA instability elements to regulate virus expression. Mol Cell Biol. 2003;23:6618-30 pubmed
    ..Thus, p54nrb and PSF have properties of key factors mediating INS function and likely define a novel mRNA regulatory pathway that is hijacked by HIV-1. ..
  23. Hakata Y, Yamada M, Mabuchi N, Shida H. The carboxy-terminal region of the human immunodeficiency virus type 1 protein Rev has multiple roles in mediating CRM1-related Rev functions. J Virol. 2002;76:8079-89 pubmed
    ..These results indicate the functional importance of the C-terminal region for full Rev activity, which leads to efficient HIV-1 replication...
  24. Bobbitt K, Addo M, Altfeld M, Filzen T, Onafuwa A, Walker B, et al. Rev activity determines sensitivity of HIV-1-infected primary T cells to CTL killing. Immunity. 2003;18:289-99 pubmed
    ..Thus, rev alleles with low activity may have a selective advantage in infected people with effective immune responses. ..
  25. Brice P, Kelley A, Butler P. Sensitive in vitro analysis of HIV-1 Rev multimerization. Nucleic Acids Res. 1999;27:2080-5 pubmed
    ..In contrast, M4 is multimerization deficient, as previously reported. Therefore, whilethe sites are correctly defined, it is inappropriate to employ the original M7 deletion mutant to study Rev oligomerization. ..
  26. Black A, Luo J, Chun S, Bakker A, Fraser J, Rosenblatt J. Specific binding of polypyrimidine tract binding protein and hnRNP A1 to HIV-1 CRS elements. Virus Genes. 1996;12:275-85 pubmed
    ..Binding by both hnRNP I and hnRNP A1 to HIV-1 and HTLV-II CRS RNAs suggests a role for these proteins in CRS function that may be influenced by the Rev and Rex proteins, respectively. ..
  27. Fankhauser C, Izaurralde E, Adachi Y, Wingfield P, Laemmli U. Specific complex of human immunodeficiency virus type 1 rev and nucleolar B23 proteins: dissociation by the Rev response element. Mol Cell Biol. 1991;11:2567-75 pubmed
    ..B23 may also serve as a shuttle for the import of HIV Rev from the cytoplasm into the nucleus or nucleolus to allow further rounds of export of RRE-containing viral RNAs. ..
  28. Dundr M, Leno G, Hammarskjold M, Rekosh D, Helga Maria C, Olson M. The roles of nucleolar structure and function in the subcellular location of the HIV-1 Rev protein. J Cell Sci. 1995;108 ( Pt 8):2811-23 pubmed
    ..These results suggest that the nucleolar location of Rev depends on continuous preribosomal RNA transcription and a substantially intact nucleolar structure. ..
  29. Fridell R, Bogerd H, Cullen B. Nuclear export of late HIV-1 mRNAs occurs via a cellular protein export pathway. Proc Natl Acad Sci U S A. 1996;93:4421-4 pubmed
  30. Wolff B, Sanglier J, Wang Y. Leptomycin B is an inhibitor of nuclear export: inhibition of nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent mRNA. Chem Biol. 1997;4:139-47 pubmed
    ..Leptomycin B is the first low molecular weight inhibitor of nuclear export to be identified. Although it cannot be used therapeutically, it should serve as a valuable tool for dissecting nuclear export pathways. ..
  31. Stutz F, Kantor J, Zhang D, McCarthy T, Neville M, Rosbash M. The yeast nucleoporin rip1p contributes to multiple export pathways with no essential role for its FG-repeat region. Genes Dev. 1997;11:2857-68 pubmed
    ..Finally, this domain of Rip1p also contributes to Rev-mediated RNA export. The data suggest that Rip1p promotes the nuclear export of different classes of substrates by contributing to optimal pore function. ..
  32. Neville M, Stutz F, Lee L, Davis L, Rosbash M. The importin-beta family member Crm1p bridges the interaction between Rev and the nuclear pore complex during nuclear export. Curr Biol. 1997;7:767-75 pubmed
    ..Our findings also agree well with current experiments on Crm1p orthologs in Schizosaccharomyces pombe and in vertebrate systems. ..
  33. Pollard V, Malim M. The HIV-1 Rev protein. Annu Rev Microbiol. 1998;52:491-532 pubmed
    ..HIV-1 Rev therefore represents an excellent system with which to study aspects of transport across the nuclear envelope. ..
  34. Najera I, Krieg M, Karn J. Synergistic stimulation of HIV-1 rev-dependent export of unspliced mRNA to the cytoplasm by hnRNP A1. J Mol Biol. 1999;285:1951-64 pubmed
    ..We conclude that hnRNP A1 is able to direct unspliced globin pre-mRNA into a nuclear compartment where it is recognised by Rev and then transported to the cytoplasm. ..
  35. Baccam P, Thompson R, Li Y, Sparks W, Belshan M, Dorman K, et al. Subpopulations of equine infectious anemia virus Rev coexist in vivo and differ in phenotype. J Virol. 2003;77:12122-31 pubmed
    ..A quasispecies model with multiple subpopulations may provide additional insight into the nature of lentivirus reservoirs and the evolution of antigenic and drug-resistant variants...
  36. Fischer U, Huber J, Boelens W, Mattaj I, Luhrmann R. The HIV-1 Rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs. Cell. 1995;82:475-83 pubmed
    ..BSA-R was itself exported from the nucleus in an active, saturable manner. Thus, the Rev activation domain constitutes a nuclear export signal that redirects RRE-containing viral RNAs to a non-mRNA export pathway. ..
  37. Wagner R, Graf M, Bieler K, Wolf H, Grunwald T, Foley P, et al. Rev-independent expression of synthetic gag-pol genes of human immunodeficiency virus type 1 and simian immunodeficiency virus: implications for the safety of lentiviral vectors. Hum Gene Ther. 2000;11:2403-13 pubmed
    ..By eliminating regions of homology and sequences involved in packaging, synthetic gag-pol genes should improve the safety profile of lentiviral vectors. ..
  38. Yu Z, Sánchez Velar N, Catrina I, Kittler E, Udofia E, Zapp M. The cellular HIV-1 Rev cofactor hRIP is required for viral replication. Proc Natl Acad Sci U S A. 2005;102:4027-32 pubmed
    ..Because hRIP is not required for cell viability, it may be an attractive target for the development of new antiviral strategies. ..
  39. Szebeni A, Herrera J, Olson M. Interaction of nucleolar protein B23 with peptides related to nuclear localization signals. Biochemistry. 1995;34:8037-42 pubmed
    ..Phosphorylation of protein B23 by casein kinase II enhanced its affinity for the SV40 T- and Rev-derived peptides approximately 2-fold.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  40. Kalland K, Szilvay A, Brokstad K, Saetrevik W, Haukenes G. The human immunodeficiency virus type 1 Rev protein shuttles between the cytoplasm and nuclear compartments. Mol Cell Biol. 1994;14:7436-44 pubmed
    ..The results show that Rev has the potential to interfere specifically with the splicing of the HIV pre-mRNA in the nucleoplasm and, next, guide such mRNAs to the cytoplasm for translation. ..
  41. Swanson C, Puffer B, Ahmad K, Doms R, Malim M. Retroviral mRNA nuclear export elements regulate protein function and virion assembly. EMBO J. 2004;23:2632-40 pubmed
    ..Thus, protein function and fate may depend upon the full and precise history of its encoding mRNA. ..
  42. Tange T, Jensen T, Kjems J. In vitro interaction between human immunodeficiency virus type 1 Rev protein and splicing factor ASF/SF2-associated protein, p32. J Biol Chem. 1996;271:10066-72 pubmed
    ..Our data are consistent with a model in which p32 functions as a link between Rev and the cellular splicing apparatus. ..
  43. Chung H -, Derse D. Binding sites for Rev and ASF/SF2 map to a 55-nucleotide purine-rich exonic element in equine infectious anemia virus RNA. J Biol Chem. 2001;276:18960-7 pubmed
    ..These data suggest that EIAV Rev-induced exon skipping observed in vivo may be initiated by simultaneous binding of Rev and SR proteins to the RRE that alter the subsequent assembly or catalytic activity of the spliceosomal complex...
  44. Schatz O, Oft M, Dascher C, Schebesta M, Rosorius O, Jaksche H, et al. Interaction of the HIV-1 rev cofactor eukaryotic initiation factor 5A with ribosomal protein L5. Proc Natl Acad Sci U S A. 1998;95:1607-12 pubmed
    ..Our data suggest that the Rev export pathway shares components of a cellular transport system involved in the intracellular trafficking of polymerase III (5S rRNA) transcripts. ..
  45. Fritz C, Green M. HIV Rev uses a conserved cellular protein export pathway for the nucleocytoplasmic transport of viral RNAs. Curr Biol. 1996;6:848-54 pubmed
    ..Finally, our experiment suggests a mechanism by which I kappa B can downregulate nuclear NF kappa B activity by causing its rapid export from the nucleus. ..
  46. Reddy T, Xu W, Wong Staal F. General effect of Sam68 on Rev/Rex regulated expression of complex retroviruses. Oncogene. 2000;19:4071-4 pubmed
    ..Thus, Sam68 may play an important role in the post-transcriptional regulation of all complex retroviruses. Oncogene (2000) 19, 4071 - 4074..
  47. Kimura T, Hashimoto I, Nishikawa M, Fujisawa J. A role for Rev in the association of HIV-1 gag mRNA with cytoskeletal beta-actin and viral protein expression. Biochimie. 1996;78:1075-80 pubmed
  48. Wolff H, Brack Werner R, Neumann M, Werner T, Schneider R. Integrated functional and bioinformatics approach for the identification and experimental verification of RNA signals: application to HIV-1 INS. Nucleic Acids Res. 2003;31:2839-51 pubmed
    ..Inhibitory activity increased by combining both INS regions in the same mRNA. Inhibitory activity of known and new INS regions was overcome by co-expression of the HIV-1 Rev protein. ..
  49. Szebeni A, Olson M. Nucleolar protein B23 has molecular chaperone activities. Protein Sci. 1999;8:905-12 pubmed
    ..Thus, by several criteria, protein B23 behaves like a molecular chaperone; these activities may be related to its role in ribosome biogenesis. ..
  50. Li J, Liu Y, Park I, He J. Expression of exogenous Sam68, the 68-kilodalton SRC-associated protein in mitosis, is able to alleviate impaired Rev function in astrocytes. J Virol. 2002;76:4526-35 pubmed
  51. Asai K, Platt C, Cochrane A. Control of HIV-1 env RNA splicing and transport: investigating the role of hnRNP A1 in exon splicing silencer (ESS3a) function. Virology. 2003;314:229-42 pubmed
    ..Consistent with this hypothesis, replacement of ESS3a with consensus hnRNP A1 binding sites was found to be insufficient to block Rev-mediated RNA export. ..
  52. Miyazaki Y, Takamatsu T, Nosaka T, Fujita S, Martin T, Hatanaka M. The cytotoxicity of human immunodeficiency virus type 1 Rev: implications for its interaction with the nucleolar protein B23. Exp Cell Res. 1995;219:93-101 pubmed
  53. Reddy T, Xu W, Mau J, Goodwin C, Suhasini M, Tang H, et al. Inhibition of HIV replication by dominant negative mutants of Sam68, a functional homolog of HIV-1 Rev. Nat Med. 1999;5:635-42 pubmed
    ..These mutants also inhibited wild-type HIV-1 replication to the same extent as the RevM10 mutant, and may be useful as anti-viral agents in the treatment of AIDS. ..