Gene expression of the human immunodeficiency virus type 1 (HIV-1) is a highly regulated process. Basal transcription of the integrated provirus generates early transcripts that encode for the viral products Tat and Rev. Tat promotes the elongation of RNA polymerase while Rev mediates the nuclear export of viral RNAs that contain the Rev-responsive RNA element (RRE). These RNAs are exported from the nucleus to allow expression of Gag-Pol and Env proteins and for the production of full-length genomic RNAs. A balance exists between completely processed mRNAs and RRE-containing RNAs. Rev functions as an adaptor that recruits cellular factors to re-direct singly spliced and unspliced viral RNAs to nuclear export. The aim of this review is to address the dynamic regulation of this post-transcriptional pathway in light of recent findings that implicate several novel cellular cofactors of Rev function.
References
[1]
Greene, W.C.; Peterlin, B.M. Charting HIV’s remarkable voyage through the cell: Basic science as a passport to future therapy. Nat. Med. 2002, 8, 673–680, doi:10.1038/nm0702-673.
[2]
Marcello, A.; Lusic, M.; Pegoraro, G.; Pellegrini, V.; Beltram, F.; Giacca, M. Nuclear organization and the control of HIV-1 transcription. Gene 2004, 326, 1–11, doi:10.1016/j.gene.2003.10.018.
[3]
Nekhai, S.; Jeang, K.T. Transcriptional and post-transcriptional regulation of HIV-1 gene expression: Role of cellular factors for Tat and Rev. Future Microbiol. 2006, 1, 417–426, doi:10.2217/17460913.1.4.417.
[4]
Karn, J.; Stoltzfus, C.M. Transcriptional and Posttranscriptional Regulation of HIV-1 Gene Expression. Cold Spring Harb. Perspect. Med. 2012, 2, 1–17.
[5]
Karn, J. The molecular biology of HIV latency: Breaking and restoring the Tat-dependent transcriptional circuit. Curr. Opin. HIV AIDS 2011, 6, 4–11, doi:10.1097/COH.0b013e328340ffbb.
[6]
Han, Y.; Wind-Rotolo, M.; Yang, H.C.; Siliciano, J.D.; Siliciano, R.F. Experimental approaches to the study of HIV-1 latency. Nat. Rev. Microbiol. 2007, 5, 95–106, doi:10.1038/nrmicro1580.
[7]
Marcello, A. Latency: The hidden HIV-1 challenge. Retrovirology 2006, 3, 7, doi:10.1186/1742-4690-3-7.
[8]
Dinoso, J.B.; Kim, S.Y.; Wiegand, A.M.; Palmer, S.E.; Gange, S.J.; Cranmer, L.; O’Shea, A.; Callender, M.; Spivak, A.; Brennan, T.; et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc. Natl. Acad. Sci. USA 2009, 106, 9403–9408.
[9]
Yukl, S.A.; Shergill, A.K.; McQuaid, K.; Gianella, S.; Lampiris, H.; Hare, C.B.; Pandori, M.; Sinclair, E.; Gunthard, H.F.; Fischer, M.; et al. Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy. AIDS 2010, 24, 2451–2460.
[10]
Gandhi, R.T.; Zheng, L.; Bosch, R.J.; Chan, E.S.; Margolis, D.M.; Read, S.; Kallungal, B.; Palmer, S.; Medvik, K.; Lederman, M.M.; et al. The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: A randomized controlled trial. PLoS Med. 2010, 7, 8.
[11]
Palmer, S.; Josefsson, L.; Coffin, J.M. HIV reservoirs and the possibility of a cure for HIV infection. J. Intern. Med. 2011, 270, 550–560, doi:10.1111/j.1365-2796.2011.02457.x.
[12]
Colin, L.; van Lint, C. Molecular control of HIV-1 postintegration latency: Implications for the development of new therapeutic strategies. Retrovirology 2009, 6, 111, doi:10.1186/1742-4690-6-111.
[13]
Stoltzfus, C.M. Chapter 1. Regulation of HIV-1 alternative RNA splicing and its role in virus replication. Adv. Virus Res. 2009, 74, 1–40, doi:10.1016/S0065-3527(09)74001-1.
[14]
Cochrane, A.W.; McNally, M.T.; Mouland, A.J. The retrovirus RNA trafficking granule: From birth to maturity. Retrovirology 2006, 3, 18, doi:10.1186/1742-4690-3-18.
[15]
Ott, M.; Geyer, M.; Zhou, Q. The control of HIV transcription: Keeping RNA polymerase II on track. Cell Host Microbe 2012, 10, 426–435.
[16]
Peterlin, B.M.; Price, D.H. Controlling the elongation phase of transcription with P-TEFb. Mol. Cell 2006, 23, 297–305, doi:10.1016/j.molcel.2006.06.014.
[17]
Jeang, K.T.; Xiao, H.; Rich, E.A. Multifaceted activities of the HIV-1 transactivator of transcription. Tat. J. Biol. Chem. 1999, 274, 28837–28840, doi:10.1074/jbc.274.41.28837.
[18]
Marcello, A.; Zoppe, M.; Giacca, M. Multiple modes of transcriptional regulation by the HIV-1 Tat transactivator. IUBMB Life 2001, 51, 175–181, doi:10.1080/152165401753544241.
[19]
Zapp, M.L.; Green, M.R. Sequence-specific RNA binding by the HIV-1 Rev protein. Nature 1989, 342, 714–716.
[20]
Kjems, J.; Brown, M.; Chang, D.D.; Sharp, P.A. Structural analysis of the interaction between the human immunodeficiency virus Rev protein and the Rev response element. Proc. Natl. Acad. Sci. USA 1991, 88, 683–687.
[21]
Chang, D.D.; Sharp, P.A. Regulation by HIV Rev depends upon recognition of splice sites. Cell 1989, 59, 789–795, doi:10.1016/0092-8674(89)90602-8.
Schroder, A.R.; Shinn, P.; Chen, H.; Berry, C.; Ecker, J.R.; Bushman, F. HIV-1 integration in the human genome favors active genes and local hotspots. Cell 2002, 110, 521–529, doi:10.1016/S0092-8674(02)00864-4.
[27]
Dieudonne, M.; Maiuri, P.; Biancotto, C.; Knezevich, A.; Kula, A.; Lusic, M.; Marcello, A. Transcriptional competence of the integrated HIV-1 provirus at the nuclear periphery. EMBO J. 2009, 28, 2231–2243, doi:10.1038/emboj.2009.141.
[28]
Marcello, A.; Dhir, S.; Dieudonne, M. Nuclear positional control of HIV transcription in 4D. Nucleus 2010, 1, 8–11.
[29]
Maiuri, P.; Knezevich, A.; Bertrand, E.; Marcello, A. Real-time imaging of the HIV-1 transcription cycle in single living cells. Methods 2011, 53, 62–67, doi:10.1016/j.ymeth.2010.06.015.
[30]
Boireau, S.; Maiuri, P.; Basyuk, E.; de la Mata, M.; Knezevich, A.; Pradet-Balade, B.; Backer, V.; Kornblihtt, A.; Marcello, A.; Bertrand, E. The transcriptional cycle of HIV-1 in real-time and live cells. J. Cell Biol. 2007, 179, 291–304, doi:10.1083/jcb.200706018.
[31]
Molle, D.; Maiuri, P.; Boireau, S.; Bertrand, E.; Knezevich, A.; Marcello, A.; Basyuk, E. A real-time view of the TAR:Tat:P-TEFb complex at HIV-1 transcription sites. Retrovirology 2007, 4, 36, doi:10.1186/1742-4690-4-36.
[32]
De Marco, A.; Biancotto, C.; Knezevich, A.; Maiuri, P.; Vardabasso, C.; Marcello, A. Intragenic transcriptional cis-activation of the human immunodeficiency virus 1 does not result in allele-specific inhibition of the endogenous gene. Retrovirology 2008, 5, 98, doi:10.1186/1742-4690-5-98.
[33]
Maiuri, P.; Knezevich, A.; De Marco, A.; Mazza, D.; Kula, A.; McNally, J.G.; Marcello, A. Fast transcription rates of RNA polymerase II in human cells. EMBO Rep. 2011, 12, 1280–1285, doi:10.1038/embor.2011.196.
[34]
Marcello, A. RNA polymerase II transcription on the fast lane. Transcription 2012, 3, 29–34, doi:10.4161/trns.3.1.19147.
[35]
Kula, A.; Guerra, J.; Knezevich, A.; Kleva, D.; Myers, M.P.; Marcello, A. Characterization of the HIV-1 RNA associated proteome identifies Matrin 3 as a nuclear cofactor of Rev function. Retrovirology 2011, 8, 60, doi:10.1186/1742-4690-8-60.
[36]
Purcell, D.F.; Martin, M.A. Alternative splicing of human immunodeficiency virus type 1 mRNA modulates viral protein expression, replication, and infectivity. J. Virol. 1993, 67, 6365–6378.
[37]
Schwartz, S.; Felber, B.K.; Benko, D.M.; Fenyo, E.M.; Pavlakis, G.N. Cloning and functional analysis of multiply spliced mRNA species of human immunodeficiency virus type 1. J. Virol. 1990, 64, 2519–2529.
[38]
Staffa, A.; Cochrane, A. Identification of positive and negative splicing regulatory elements within the terminal tat-rev exon of human immunodeficiency virus type 1. Mol. Cell Biol. 1995, 15, 4597–4605.
[39]
Staffa, A.; Cochrane, A. The tat/rev intron of human immunodeficiency virus type 1 is inefficiently spliced because of suboptimal signals in the 3' splice site. J. Virol. 1994, 68, 3071–3079.
[40]
Dyhr-Mikkelsen, H.; Kjems, J. Inefficient spliceosome assembly and abnormal branch site selection in splicing of an HIV-1 transcript in vitro. J. Biol. Chem. 1995, 270, 24060–24066.
[41]
O'Reilly, M.M.; McNally, M.T.; Beemon, K.L. Two strong 5' splice sites and competing, suboptimal 3' splice sites involved in alternative splicing of human immunodeficiency virus type 1 RNA. Virology 1995, 213, 373–385, doi:10.1006/viro.1995.0010.
[42]
Si, Z.; Amendt, B.A.; Stoltzfus, C.M. Splicing efficiency of human immunodeficiency virus type 1 tat RNA is determined by both a suboptimal 3' splice site and a 10 nucleotide exon splicing silencer element located within tat exon 2. Nucleic Acids Res. 1997, 25, 861–867, doi:10.1093/nar/25.4.861.
[43]
Amendt, B.A.; Si, Z.H.; Stoltzfus, C.M. Presence of exon splicing silencers within human immunodeficiency virus type 1 tat exon 2 and tat-rev exon 3: Evidence for inhibition mediated by cellular factors. Mol. Cell Biol. 1995, 15, 4606–4615.
[44]
Amendt, B.A.; Hesslein, D.; Chang, L.J.; Stoltzfus, C.M. Presence of negative and positive cis-acting RNA splicing elements within and flanking the first tat coding exon of human immunodeficiency virus type 1. Mol. Cell Biol. 1994, 14, 3960–3970.
[45]
Caputi, M.; Mayeda, A.; Krainer, A.R.; Zahler, A.M. hnRNP A/B proteins are required for inhibition of HIV-1 pre-mRNA splicing. Embo. J. 1999, 18, 4060–4067, doi:10.1093/emboj/18.14.4060.
[46]
Tange, T.O.; Damgaard, C.K.; Guth, S.; Valcarcel, J.; Kjems, J. The hnRNP A1 protein regulates HIV-1 tat splicing via a novel intron silencer element. Embo. J. 2001, 20, 5748–5758, doi:10.1093/emboj/20.20.5748.
[47]
Cochrane, A.W.; Jones, K.S.; Beidas, S.; Dillon, P.J.; Skalka, A.M.; Rosen, C.A. Identification and characterization of intragenic sequences which repress human immunodeficiency virus structural gene expression. J. Virol. 1991, 65, 5305–5313.
[48]
Maldarelli, F.; Martin, M.A.; Strebel, K. Identification of posttranscriptionally active inhibitory sequences in human immunodeficiency virus type 1 RNA: Novel level of gene regulation. J. Virol. 1991, 65, 5732–5743.
[49]
Nasioulas, G.; Zolotukhin, A.S.; Tabernero, C.; Solomin, L.; Cunningham, C.P.; Pavlakis, G.N.; Felber, B.K. Elements distinct from human immunodeficiency virus type 1 splice sites are responsible for the Rev dependence of env mRNA. J. Virol. 1994, 68, 2986–2993.
[50]
Schneider, R.; Campbell, M.; Nasioulas, G.; Felber, B.K.; Pavlakis, G.N. Inactivation of the human immunodeficiency virus type 1 inhibitory elements allows Rev-independent expression of Gag and Gag/protease and particle formation. J. Virol. 1997, 71, 4892–4903.
[51]
Schwartz, S.; Campbell, M.; Nasioulas, G.; Harrison, J.; Felber, B.K.; Pavlakis, G.N. Mutational inactivation of an inhibitory sequence in human immunodeficiency virus type 1 results in Rev-independent gag expression. J. Virol. 1992, 66, 7176–7182.
[52]
Mikaelian, I.; Krieg, M.; Gait, M.J.; Karn, J. Interactions of INS (CRS) elements and the splicing machinery regulate the production of Rev-responsive mRNAs. J. Mol. Biol. 1996, 257, 246–264, doi:10.1006/jmbi.1996.0160.
[53]
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, 1951–1964, doi:10.1006/jmbi.1998.2473.
[54]
Afonina, E.; Neumann, M.; Pavlakis, G.N. Preferential binding of poly(A)-binding protein 1 to an inhibitory RNA element in the human immunodeficiency virus type 1 gag mRNA. J. Biol. Chem. 1997, 272, 2307–2311.
[55]
Black, A.C.; Luo, J.; Chun, S.; Bakker, A.; Fraser, J.K.; Rosenblatt, J.D. Specific binding of polypyrimidine tract binding protein and hnRNP A1 to HIV-1 CRS elements. Virus Genes 1996, 12, 275–285.
[56]
Zolotukhin, A.S.; Michalowski, D.; Bear, J.; Smulevitch, S.V.; Traish, A.M.; Peng, R.; Patton, J.; Shatsky, I.N.; Felber, B.K. PSF acts through the human immunodeficiency virus type 1 mRNA instability elements to regulate virus expression. Mol. Cell Biol. 2003, 23, 6618–6630.
[57]
Sodroski, J.; Goh, W.C.; Rosen, C.; Dayton, A.; Terwilliger, E.; Haseltine, W. A second post-transcriptional trans-activator gene required for HTLV-III replication. Nature 1986, 321, 412–417.
[58]
Feinberg, M.B.; Jarrett, R.F.; Aldovini, A.; Gallo, R.C.; Wong-Staal, F. HTLV-II expression and production involve complex regulation at the levels of splicing and translation of viral RNA. Cell 1986, 46, 807–817, doi:10.1016/0092-8674(86)90062-0.
[59]
Meggio, F.; D'Agostino, D.M.; Ciminale, V.; Chieco-Bianchi, L.; Pinna, L.A. Phosphorylation of HIV-1 Rev protein: Implication of protein kinase CK2 and pro-directed kinases. Biochem Biophys Res Commun 1996, 226, 547–554, doi:10.1006/bbrc.1996.1392.
[60]
Invernizzi, C.F.; Xie, B.; Richard, S.; Wainberg, M.A. PRMT6 diminishes HIV-1 Rev binding to and export of viral RNA. Retrovirology 2006, 3, 93, doi:10.1186/1742-4690-3-93.
[61]
Groom, H.C.; Anderson, E.C.; Lever, A.M. Rev: Beyond nuclear export. J. Gen. Virol. 2009, 90, 1303–1318, doi:10.1099/vir.0.011460-0.
[62]
Yedavalli, V.S.; Jeang, K.T. Trimethylguanosine capping selectively promotes expression of Rev-dependent HIV- RNAs. Proc. Natl. Acad. Sci. USA 2010, 107, 14787–14792, doi:10.1073/pnas.1009490107.
[63]
Grewe, B.; Uberla, K. The human immunodeficiency virus type 1 Rev protein: Menage a trois during the early phase of the lentiviral replication cycle. J. Gen. Virol. 2010, 91, 1893–1897, doi:10.1099/vir.0.022509-0.
[64]
Fornerod, M.; Ohno, M.; Yoshida, M.; Mattaj, I.W. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell 1997, 90, 1051–1060, doi:10.1016/S0092-8674(00)80371-2.
[65]
Henderson, B.R.; 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, doi:10.1006/jmbi.1997.1420.
[66]
Truant, R.; Cullen, B.R. The arginine-rich domains present in human immunodeficiency virus type 1 Tat and Rev function as direct importin beta-dependent nuclear localization signals. Mol. Cell Biol. 1999, 19, 1210–1217.
[67]
Yedavalli, V.S.; Neuveut, C.; Chi, Y.H.; Kleiman, L.; Jeang, K.T. Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function. Cell 2004, 119, 381–392, doi:10.1016/j.cell.2004.09.029.
[68]
Fang, J.; Acheampong, E.; Dave, R.; Wang, F.; Mukhtar, M.; Pomerantz, R.J. The RNA helicase DDX1 is involved in restricted HIV-1 Rev function in human astrocytes. Virology 2005, 336, 299–307, doi:10.1016/j.virol.2005.03.017.
[69]
Li, J.; Tang, H.; Mullen, T.M.; Westberg, C.; Reddy, T.R.; Rose, D.W.; Wong-Staal, F. A role for RNA helicase A in post-transcriptional regulation of HIV type 1. Proc. Natl. Acad. Sci. USA 1999, 96, 709–714.
[70]
Ma, J.; Rong, L.; Zhou, Y.; Roy, B.B.; Lu, J.; Abrahamyan, L.; Mouland, A.J.; Pan, Q.; Liang, C. The requirement of the DEAD-box protein DDX24 for the packaging of human immunodeficiency virus type 1 RNA. Virology 2008, 375, 253–264, doi:10.1016/j.virol.2008.01.025.
[71]
Fankhauser, C.; Izaurralde, E.; Adachi, Y.; Wingfield, P.; Laemmli, U.K. Specific complex of human immunodeficiency virus type 1 rev and nucleolar B23 proteins: Dissociation by the Rev response element. Mol. Cell Biol. 1991, 11, 2567–2575.
[72]
Tange, T.O.; Jensen, T.H.; 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, 10066–10072.
[73]
Cochrane, A.; Murley, L.L.; Gao, M.; Wong, R.; Clayton, K.; Brufatto, N.; Canadien, V.; Mamelak, D.; Chen, T.; Richards, D.; Zeghouf, M.; Greenblatt, J.; Burks, C.; Frappier, L. Stable complex formation between HIV Rev and the nucleosome assembly protein, NAP1, affects Rev function. Virology 2009, 388, 103–111, doi:10.1016/j.virol.2009.03.005.
[74]
Gu, L.; Tsuji, T.; Jarboui, M.A.; Yeo, G.P.; Sheehy, N.; Hall, W.W.; Gautier, V.W. Intermolecular masking of the HIV-1 Rev NLS by the cellular protein HIC: Novel insights into the regulation of Rev nuclear import. Retrovirology 2011, 8, 17, doi:10.1186/1742-4690-8-17.
[75]
Ruhl, M.; Himmelspach, M.; Bahr, G.M.; Hammerschmid, F.; Jaksche, H.; Wolff, B.; Aschauer, H.; Farrington, G.K.; Probst, H.; Bevec, D.; et al. Eukaryotic initiation factor 5A is a cellular target of the human immunodeficiency virus type 1 Rev activation domain mediating trans-activation. J. Cell Biol. 1993, 123, 1309–1320, doi:10.1083/jcb.123.6.1309.
[76]
Bevec, D.; Jaksche, H.; Oft, M.; Wohl, T.; Himmelspach, M.; Pacher, A.; Schebesta, M.; Koettnitz, K.; Dobrovnik, M.; Csonga, R.; Lottspeich, F.; Hauber, J. Inhibition of HIV-1 replication in lymphocytes by mutants of the Rev cofactor eIF-5A. Science 1996, 271, 1858–1860.
[77]
Campbell, L.H.; Borg, K.T.; Haines, J.K.; Moon, R.T.; Schoenberg, D.R.; Arrigo, S.J. Human immunodeficiency virus type 1 Rev is required in vivo for binding of poly(A)-binding protein to Rev-dependent RNAs. J. Virol. 1994, 68, 5433–5438.
[78]
Bogerd, H.P.; Fridell, R.A.; Madore, S.; Cullen, B.R. Identification of a novel cellular cofactor for the Rev/Rex class of retroviral regulatory proteins. Cell 1995, 82, 485–494, doi:10.1016/0092-8674(95)90437-9.
[79]
Fritz, C.C.; Zapp, M.L.; Green, M.R. A human nucleoporin-like protein that specifically interacts with HIV Rev. Nature 1995, 376, 530–533.
[80]
Reddy, T.R.; Xu, W.; Mau, J.K.; Goodwin, C.D.; Suhasini, M.; Tang, H.; Frimpong, K.; Rose, D.W.; Wong-Staal, F. Inhibition of HIV replication by dominant negative mutants of Sam68, a functional homolog of HIV-1 Rev. Nat. Med. 1999, 5, 635–642, doi:10.1038/9479.
[81]
Modem, S.; Badri, K.R.; Holland, T.C.; Reddy, T.R. Sam68 is absolutely required for Rev function and HIV-1 production. Nucleic Acids Res. 2005, 33, 873–879, doi:10.1093/nar/gki231.
[82]
Modem, S.; Reddy, T.R. An anti-apoptotic protein, Hax-1, inhibits the HIV-1 rev function by altering its sub-cellular localization. J. Cell Physiol. 2008, 214, 14–19.
[83]
Yedavalli, V.S.; Jeang, K.T. Matrin 3 is a co-factor for HIV-1 Rev in regulating post-transcriptional viral gene expression. Retrovirology 2011, 8, 61, doi:10.1186/1742-4690-8-61.
[84]
Powell, D.M.; Amaral, M.C.; Wu, J.Y.; Maniatis, T.; Greene, W.C. HIV Rev-dependent binding of SF2/ASF to the Rev response element: possible role in Rev-mediated inhibition of HIV RNA splicing. Proc. Natl. Acad. Sci. USA 1997, 94, 973–978.
[85]
Xu, Y.; Reddy, T.R.; Fischer, W.H.; Wong-Staal, F. A Novel hnRNP Specifically Interacts with HIV-1 RRE RNA. J. Biomed. Sci. 1996, 3, 82–91, doi:10.1007/BF02255535.
[86]
Kaminski, R.; Darbinian, N.; Sawaya, B.E.; Slonina, D.; Amini, S.; Johnson, E.M.; Rappaport, J.; Khalili, K.; Darbinyan, A. Puralpha as a cellular co-factor of Rev/RRE-mediated expression of HIV-1 intron-containing mRNA. J. Cell Biochem. 2008, 103, 1231–1245, doi:10.1002/jcb.21503.
[87]
Kubota, S.; Adachi, Y.; Copeland, T.D.; Oroszlan, S. Binding of human prothymosin alpha to the leucine-motif/activation domains of HTLV-I Rex and HIV-1 Rev. Eur. J. Biochem. 1995, 233, 48–54.
[88]
Urcuqui-Inchima, S.; Castano, M.E.; Hernandez-Verdun, D.; St-Laurent, G., 3rd; Kumar, A. Nuclear Factor 90, a cellular dsRNA binding protein inhibits the HIV Rev-export function. Retrovirology 2006, 3, 83, doi:10.1186/1742-4690-3-83.
[89]
Wu, B.Y.; Woffendin, C.; Duckett, C.S.; Ohno, T.; Nabel, G.J. Regulation of human retroviral latency by the NF-kappa B/I kappa B family: Inhibition of human immunodeficiency virus replication by I kappa B through a Rev-dependent mechanism. Proc. Natl. Acad. Sci. USA 1995, 92, 1480–1484.
[90]
Kramer-Hammerle, S.; Ceccherini-Silberstein, F.; Bickel, C.; Wolff, H.; Vincendeau, M.; Werner, T.; Erfle, V.; Brack-Werner, R. Identification of a novel Rev-interacting cellular protein. BMC Cell Biol. 2005, 6, 20, doi:10.1186/1471-2121-6-20.
[91]
Ariumi, Y.; Trono, D. Ataxia-telangiectasia-mutated (ATM) protein can enhance human immunodeficiency virus type 1 replication by stimulating Rev function. J. Virol. 2006, 80, 2445–2452, doi:10.1128/JVI.80.5.2445-2452.2006.
[92]
Kimura, T.; Hashimoto, I.; Nishikawa, M.; Fujisawa, J.I. A role for Rev in the association of HIV-1 gag mRNA with cytoskeletal beta-actin and viral protein expression. Biochimie 1996, 78, 1075–1080, doi:10.1016/S0300-9084(97)86732-6.
[93]
Hofmann, W.; Reichart, B.; Ewald, A.; Muller, E.; Schmitt, I.; Stauber, R.H.; Lottspeich, F.; Jockusch, B.M.; Scheer, U.; Hauber, J.; Dabauvalle, M.C. Cofactor requirements for nuclear export of Rev response element (RRE)- and constitutive transport element (CTE)-containing retroviral RNAs. An unexpected role for actin. J. Cell Biol. 2001, 152, 895–910, doi:10.1083/jcb.152.5.895.
[94]
Askjaer, P.; Jensen, T.H.; 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, 33414–33422.
[95]
Brennan, C.M.; Gallouzi, I.E.; Steitz, J.A. Protein ligands to HuR modulate its interaction with target mRNAs in vivo. J. Cell Biol. 2000, 151, 1–14.
[96]
Jeang, K.T.; Yedavalli, V. Role of RNA helicases in HIV-1 replication. Nucleic Acids Res. 2006, 34, 4198–4205, doi:10.1093/nar/gkl398.
[97]
Fang, J.; Kubota, S.; Yang, B.; Zhou, N.; Zhang, H.; Godbout, R.; Pomerantz, R.J. A DEAD box protein facilitates HIV-1 replication as a cellular co-factor of Rev. Virology 2004, 330, 471–480, doi:10.1016/j.virol.2004.09.039.
[98]
Dundr, M.; Leno, G.H.; Hammarskjold, M.L.; Rekosh, D.; Helga-Maria, C.; Olson, M.O. The roles of nucleolar structure and function in the subcellular location of the HIV-1 Rev protein. J. Cell Sci. 1995, 108, 2811–2823.
[99]
Zheng, Y.H.; Yu, H.F.; Peterlin, B.M. Human p32 protein relieves a post-transcriptional block to HIV replication in murine cells. Nat. Cell Biol. 2003, 5, 611–618, doi:10.1038/ncb1000.
[100]
Li, Y.P. Protein B23 is an important human factor for the nucleolar localization of the human immunodeficiency virus protein Tat. J. Virol. 1997, 71, 4098–4102.
[101]
Gautier, V.W.; Sheehy, N.; Duffy, M.; Hashimoto, K.; Hall, W.W. Direct interaction of the human I-mfa domain-containing protein, HIC, with HIV-1 Tat results in cytoplasmic sequestration and control of Tat activity. Proc. Natl. Acad. Sci. USA 2005, 102, 16362–16367.
[102]
Berro, R.; Kehn, K.; de la Fuente, C.; Pumfery, A.; Adair, R.; Wade, J.; Colberg-Poley, A.M.; Hiscott, J.; Kashanchi, F. Acetylated Tat regulates human immunodeficiency virus type 1 splicing through its interaction with the splicing regulator p32. J. Virol. 2006, 80, 3189–3204.
[103]
Vardabasso, C.; Manganaro, L.; Lusic, M.; Marcello, A.; Giacca, M. The histone chaperone protein Nucleosome Assembly Protein-1 (hNAP-1) binds HIV-1 Tat and promotes viral transcription. Retrovirology 2008, 5, 8, doi:10.1186/1742-4690-5-8.
[104]
De Marco, A.; Dans, P.D.; Knezevich, A.; Maiuri, P.; Pantano, S.; Marcello, A. Subcellular localization of the interaction between the human immunodeficiency virus transactivator Tat and the nucleosome assembly protein 1. Amino Acids 2010, 38, 1583–1593, doi:10.1007/s00726-009-0378-9.
[105]
Sanchez-Velar, N.; Udofia, E.B.; Yu, Z.; Zapp, M.L. hRIP, a cellular cofactor for Rev function, promotes release of HIV RNAs from the perinuclear region. Genes Dev. 2004, 18, 23–34, doi:10.1101/gad.1149704.
[106]
Yu, Z.; Sanchez-Velar, N.; Catrina, I.E.; Kittler, E.L.; Udofia, E.B.; Zapp, M.L. The cellular HIV-1 Rev cofactor hRIP is required for viral replication. Proc. Natl. Acad. Sci. USA 2005, 102, 4027–4032.
[107]
Zhang, Z.; Carmichael, G.G. The fate of dsRNA in the nucleus: a p54(nrb)-containing complex mediates the nuclear retention of promiscuously A-to-I edited RNAs. Cell 2001, 106, 465–475, doi:10.1016/S0092-8674(01)00466-4.
[108]
Cronshaw, J.M.; Krutchinsky, A.N.; Zhang, W.; Chait, B.T.; Matunis, M.J. Proteomic analysis of the mammalian nuclear pore complex. J. Cell Biol. 2002, 158, 915–927, doi:10.1083/jcb.200206106.
[109]
Naji, S.; Ambrus, G.; Cimermancic, P.; Reyes, J.R.; Johnson, J.R.; Filbrandt, R.; Huber, M.D.; Vesely, P.; Krogan, N.J.; Yates, J.R.; Saphire, A.C.; Gerace, L. Host cell interactome of HIV-1 Rev includes RNA helicases involved in multiple facets of virus production. Mol. Cell Prot. 2012, 11, M111–015313, doi:10.1074/mcp.M111.015313.
Iacampo, S.; Cochrane, A. Human immunodeficiency virus type 1 Rev function requires continued synthesis of its target mRNA. J. Virol. 1996, 70, 8332–8339.
[112]
Luo, Y.; Madore, S.J.; Parslow, T.G.; Cullen, B.R.; Peterlin, B.M. Functional analysis of interactions between Tat and the trans-activation response element of human immunodeficiency virus type 1 in cells. J. Virol. 1993, 67, 5617–5622.
[113]
Southgate, C.; Zapp, M.L.; Green, M.R. Activation of transcription by HIV-1 Tat protein tethered to nascent RNA through another protein. Nature 1990, 345, 640–642.
[114]
Berthold, E.; Maldarelli, F. cis-acting elements in human immunodeficiency virus type 1 RNAs direct viral transcripts to distinct intranuclear locations. J. Virol. 1996, 70, 4667–4682.
[115]
Kalland, K.H.; Szilvay, A.M.; Langhoff, E.; Haukenes, G. Subcellular distribution of human immunodeficiency virus type 1 Rev and colocalization of Rev with RNA splicing factors in a speckled pattern in the nucleoplasm. J. Virol. 1994, 68, 1475–1485.
[116]
Wolff, B.; Cohen, G.; Hauber, J.; Meshcheryakova, D.; Rabeck, C. Nucleocytoplasmic transport of the Rev protein of human immunodeficiency virus type 1 is dependent on the activation domain of the protein. Exp. Cell Res. 1995, 217, 31–41, doi:10.1006/excr.1995.1060.
[117]
Boe, S.O.; Bjorndal, B.; Rosok, B.; Szilvay, A.M.; Kalland, K.H. Subcellular localization of human immunodeficiency virus type 1 RNAs, Rev, and the splicing factor SC-35. Virology 1998, 244, 473–482, doi:10.1006/viro.1998.9110.
[118]
Favaro, J.P.; Borg, K.T.; Arrigo, S.J.; Schmidt, M.G. Effect of Rev on the intranuclear localization of HIV-1 unspliced RNA. Virology 1998, 249, 286–296, doi:10.1006/viro.1998.9312.
[119]
Zhang, G.; Zapp, M.L.; Yan, G.; Green, M.R. Localization of HIV-1 RNA in mammalian nuclei. J. Cell Biol. 1996, 135, 9–18, doi:10.1083/jcb.135.1.9.
[120]
Pond, S.J.; Ridgeway, W.K.; Robertson, R.; Wang, J.; Millar, D.P. HIV-1 Rev protein assembles on viral RNA one molecule at a time. Proc. Natl. Acad. Sci. USA 2009, 106, 1404–1408.
[121]
Cook, K.S.; Fisk, G.J.; Hauber, J.; Usman, N.; Daly, T.J.; Rusche, J.R. Characterization of HIV-1 REV protein: Binding stoichiometry and minimal RNA substrate. Nucleic Acids Res 1991, 19, 1577–1583.
[122]
Daly, T.J.; Cook, K.S.; Gray, G.S.; Maione, T.E.; Rusche, J.R. Specific binding of HIV-1 recombinant Rev protein to the Rev-responsive element in vitro. Nature 1989, 342, 816–819.
[123]
Heaphy, S.; Dingwall, C.; Ernberg, I.; Gait, M.J.; Green, S.M.; Karn, J.; Lowe, A.D.; Singh, M.; Skinner, M.A. HIV-1 regulator of virion expression (Rev) protein binds to an RNA stem-loop structure located within the Rev response element region. Cell 1990, 60, 685–693, doi:10.1016/0092-8674(90)90671-Z.
[124]
Malim, M.H.; Tiley, L.S.; McCarn, D.F.; Rusche, J.R.; Hauber, J.; Cullen, B.R. HIV-1 structural gene expression requires binding of the Rev trans-activator to its RNA target sequence. Cell 1990, 60, 675–683, doi:10.1016/0092-8674(90)90670-A.
[125]
Madore, S.J.; Tiley, L.S.; Malim, M.H.; Cullen, B.R. Sequence requirements for Rev multimerization in vivo. Virology 1994, 202, 186–194, doi:10.1006/viro.1994.1334.
[126]
Daugherty, M.D.; Liu, B.; Frankel, A.D. Structural basis for cooperative RNA binding and export complex assembly by HIV Rev. Nat. Struct. Mol. Biol. 2010, 17, 1337–1342.
[127]
Daugherty, M.D.; Booth, D.S.; Jayaraman, B.; Cheng, Y.; Frankel, A.D. HIV Rev response element (RRE) directs assembly of the Rev homooligomer into discrete asymmetric complexes. Proc. Natl. Acad. Sci. USA 2010, 107, 12481–12486.
[128]
Daugherty, M.D.; D'Orso, I.; Frankel, A.D. A solution to limited genomic capacity: Using adaptable binding surfaces to assemble the functional HIV Rev oligomer on RNA. Mol. Cell 2008, 31, 824–834, doi:10.1016/j.molcel.2008.07.016.
[129]
DiMattia, M.A.; Watts, N.R.; Stahl, S.J.; Rader, C.; Wingfield, P.T.; Stuart, D.I.; Steven, A.C.; Grimes, J.M. Implications of the HIV-1 Rev dimer structure at 3.2 A resolution for multimeric binding to the Rev response element. Proc. Natl. Acad. Sci. USA 2010, 107, 5810–5814.
[130]
Hoffmann, D.; Schwark, D.; Banning, C.; Brennen, M.; Lakshmikanth, M.; Krepstakies, M.; Schindler, M.; Millar, D.P.; Hauber, J. Formation of trans-activation competent HIV-1 Rev: RRE complexes requires the recruitment of multiple protein activation domains. PLoS One 2012. in press.
[131]
Robertson-Anderson, R.M.; Wang, J.; Edgcomb, S.P.; Carmel, A.B.; Williamson, J.R.; Millar, D.P. Single-molecule studies reveal that DEAD box protein DDX1 promotes oligomerization of HIV-1 Rev on the Rev response element. J. Mol. Biol. 2011, 410, 959–971, doi:10.1016/j.jmb.2011.04.026.
[132]
Grunwald, D.; Singer, R.H. In vivo imaging of labelled endogenous beta-actin mRNA during nucleocytoplasmic transport. Nature 2010, 467, 604–607.
[133]
Mor, A.; Shav-Tal, Y. Dynamics and kinetics of nucleo-cytoplasmic mRNA export. Wiley Interdiscip Rev. RNA 2010, 1, 388–401, doi:10.1002/wrna.41.
[134]
Müller, B. Novel imaging technologies in the study of HIV. Future Virol. 2011, 6, 929–940, doi:10.2217/fvl.11.66.
