Chapter 6 : Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development

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This chapter discusses the potential of HIV Tat, Rev, and their cellular cofactors as drug targets. Tat interacts with numerous transcriptional regulatory factors and presumably by virtue of its interaction with transcription activation response (TAR) RNA, recruits these factors to the human immunodeficiency virus type 1 (HIV-1) promoter. Thus, HIV-1 transcription directed from the viral long terminal repeat (LTR) is balanced by the actions of kinases and phosphatases, and both can be potential targets for drug development. Tat promotes the elongation of viral transcripts by increasing the occupancy time of CDK9/cyclin T1 on the HIV-1 LTR. Small-molecule inhibitors of Tat-TAR RNA interaction, small-molecule inhibitors of CDKs such as CDK9 or CDK2, and inhibitors that disrupt the interaction of Tat with additional host cell factors such as p300/CREB binding protein-associated factor (PCAF) and/or inhibit cellular activities of the host cell factors could all be viable anti-HIV drug candidates. Both Tat and TAR RNA are essential for activated HIV-1 transcription, and were thus the first candidates to be considered for drug design that targeted HIV-1 transcription. Antiviral development against HIV-1 regulatory proteins Tat and Rev represents a conceptual work in progress. In the arena of inhibiting Tat and Rev cellular cofactors, the concerns over host toxicity have not been fully resolved. Future efforts are needed to address the two major challenges of mechanistic specificity and functional toxicity.

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6
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Image of Figure 1.
Figure 1.

Illustration of activation of HIV-1 transcription by Tat. Tat cofactors including TAR RNA that were targeted for development of specific inhibitors are indicated.

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6
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Image of Figure 2.
Figure 2.

Diagrams of Rev and RRE. (A) Schematic representation of the different protein motifs in the Rev protein; (B) secondary structure of the RRE RNA that is the target for Rev function.

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6
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Image of Figure 3.
Figure 3.

Cartoon of Rev function in exporting unspliced HIV-1 RNAs. Different steps of Rev activity are indicated as potential points for inhibition of function.

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6
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1. Agbottah, E.,, C. de La Fuente,, S. Nekhai,, A. Barnett,, A. Gianella-Borradori,, A. Pumfery, and, F. Kashanchi. 2005. Antiviral activity of CYC202 in HIV-1-infected cells. J. Biol. Chem. 280: 30293042.
2. Agbottah, E.,, N. Zhang,, S. Dadgar,, A. Pumfery,, J. D. Wade,, C. Zeng, and, F. Kashanchi. 2006. Inhibition of HIV-1 virus replication using small soluble Tat peptides. Virology 345: 373389.
3. Aklilu, M.,, H. L. Kindler,, R. C. Donehower,, S. Mani,and, E. E. Vokes. 2003. Phase II study of flavopiridol in patients with advanced colorectal cancer. Ann. Oncol. 14: 12701273.
4. Ammosova, T.,, R. Berro,, M. Jerebtsova,, A. Jackson,, S. Charles,, Z. Klase,, W. Southerland,, V. R. Gordeuk,, F. Kashanchi, and, S. Nekhai. 2006. Phosphorylation of HIV-1 Tat by CDK2 in HIV-1 transcription. Retrovirology 3: 78.
5. Ammosova, T.,, R. Berro,, F. Kashanchi, and, S. Nekhai. 2005. RNA interference directed to CDK2 inhibits HIV-1 transcription. Virology 341: 171178.
6. Ammosova, T.,, M. Jerebtsova,, M. Beullens,, B. Lesage,, A. Jackson,, F. Kashanchi,, W. Southerland,, V. R. Gordeuk,, M. Bollen, and, S. Nekhai. 2005. Nuclear targeting of protein phosphatase-1 by HIV-1 Tat protein. J. Biol. Chem. 280: 3636436371.
7. Ammosova, T.,, M. Jerebtsova,, M. Beullens,, Y. Voloshin,, P. E. Ray,, A. Kumar,, M. Bollen, and, S. Nekhai. 2003. Nuclear protein phosphatase-1 regulates HIV-1 transcription. J. Biol. Chem. 278: 3218932194.
8. Ammosova, T.,, K. Washington,, Z. Debebe,, J. Brady, and, S. Nekhai. 2005. Dephosphorylation of CDK9 by protein phosphatase 2A and protein phosphatase-1 in Tat-activated HIV-1 transcription. Retrovirology 2: 47.
9. Andrews, M. J.,, G. Kontopidis,, C. McInnes,, A. Plater,, L. Innes,, A. Cowan,, P. Jewsbury,and, P. M. Fischer. 2006. REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors. Chembiochem 7: 19091915.
10. Athanassiou, Z.,, K. Patora,, R. L. Dias,, K. Moehle,, J. A. Robinson, and, G. Varani. 2007. Structure-guided peptidomimetic design leads to nanomolar beta-hairpin inhibitors of the Tat-TAR interaction of bovine immunodeficiency virus. Biochemistry 46: 741751.
11. Baldwin, C. E., and, B. Berkhout. 2007. HIV-1 drug-resistance and drug-dependence. Retrovirology 4: 78.
12. Barboric, M.,, J. H. Yik,, N. Czudnochowski,, Z. Yang,, R. Chen,, X. Contreras,, M. Geyer,, B. Matija Peterlin, and, Q. Zhou. 2007. Tat competes with HEXIM1 to increase the active pool of P-TEFb for HIV-1 transcription. Nucleic Acids Res. 35: 20032012.
13. Bharucha, D. C.,, M. Zhou,, S. Nekhai,, J. N. Brady,, R. R. Shukla, and, A. Kumar. 2002. A protein phosphatase from human T cells augments tat transactivation of the human immunodeficiency virus type 1 long-terminal repeat. Virology 296: 616.
14. Biglione, S.,, S. A. Byers,, J. P. Price,, V. T. Nguyen,, O. Bensaude,, D. H. Price, and, W. Maury. 2007. Inhibition of HIV-1 replication by P-TEFb inhibitors DRB, seliciclib and flavopiridol correlates with release of free P-TEFb from the large, inactive form of the complex. Retrovirology 4: 47.
15. Borowski, P.,, J. Deinert,, S. Schalinski,, M. Bretner,, K. Ginalski,, T. Kulikowski, and, D. Shugar. 2003. Halogenated benzimidazoles and benzotriazoles as inhibitors of the NTPase/helicase activities of hepatitis C and related viruses. Eur. J. Biochem. 270: 16451653.
16. Burdette-Radoux, S.,, R. G. Tozer,, R. C. Lohmann,, I. Quirt,, D. S. Ernst,, W. Walsh,, N. Wainman,, A. D. Colevas,and, E. A. Eisenhauer. 2004. Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma. Investig. New Drugs 22: 315322.
17. Carlson, B. A.,, M. M. Dubay,, E. A. Sausville,, L. Brizuela, and, P. J. Worland. 1996. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res. 56: 29732978.
18. Chao, S. H.,, K. Fujinaga,, J. E. Marion,, R. Taube,, E. A. Sausville,, A. M. Senderowicz,, B. M. Peterlin, and, D. H. Price. 2000. Flavopiridol inhibits P-TEFb and blocks HIV-1 replication. J. Biol. Chem. 275: 2834528348.
19. Chao, S. H., and, D. H. Price. 2001. Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J. Biol. Chem. 276: 3179331799.
20. Chapman, R. L.,, T. B. Stanley,, R. Hazen, and, E. P. Garvey. 2002. Small molecule modulators of HIV Rev/Rev response element interaction identified by random screening. Antivir. Res. 54: 149162.
21. Chaubey, B.,, S. Tripathi,, S. Ganguly,, D. Harris,, R. A. Casale, and, V. N. Pandey. 2005. A PNA-transportan conjugate targeted to the TAR region of the HIV-1 genome exhibits both antiviral and virucidal properties. Virology 331: 418428.
22. Chen, D., and, Q. Zhou. 1999. Tat activates human immunodeficiency virus type 1 transcriptional elongation independent of TFIIH kinase. Mol. Cell. Biol. 19: 28632871.
23. Chen, R.,, Z. Yang, and, Q. Zhou. 2004. Phosphorylated positive transcription elongation factor b (P-TEFb) is tagged for inhibition through association with 7SK snRNA. J. Biol. Chem. 279: 41534160.
24. Cocude, C.,, M. J. Truong,, O. Billaut-Mulot,, V. Delsart,, E. Darcissac,, A. Capron,, Y. Mouton, and, G. M. Bahr. 2003. A novel cellular RNA helicase, RH116, differentially regulates cell growth, programmed cell death and human immunodeficiency virus type 1 replication. J. Gen. Virol. 84: 32153225.
25. Crute, J. J.,, C. A. Grygon,, K. D. Hargrave,, B. Simoneau,, A. M. Faucher,, G. Bolger,, P. Kibler,, M. Liuzzi, and, M. G. Cordingley. 2002. Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease. Nat. Med. 8: 386391.
26. Daelemans, D.,, E. Afonina,, J. Nilsson,, G. Werner,, J. Kjems,, E. De Clercq,, G. N. Pavlakis, and, A. M. Vandamme. 2002. A synthetic HIV-1 Rev inhibitor interfering with the CRM1-mediated nuclear export. Proc. Natl. Acad. Sci. USA 99: 1444014445.
27. Dayton, A. I. 2004. Within you, without you: HIV-1 Rev and RNA export. Retrovirology 1: 35.
28. de Azevedo, W. F., Jr.,, F. Canduri, and, N. J. da Silveira. 2002. Structural basis for inhibition of cyclin-dependent kinase 9 by flavopiridol. Biochem. Biophys. Res. Commun. 293: 566571.
29. De Azevedo, W. F., Jr.,, H. J. Mueller-Dieckmann,, U. SchulzeGahmen,, P. J. Worland,, E. Sausville, and, S. H. Kim. 1996. Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. Proc. Natl. Acad. Sci. USA 93: 27352740.
30. Debebe, Z.,, T. Ammosova,, M. Jerebtsova,, J. Kurantsin-Mills,, X. Niu,, S. Charles,, D. R. Richardson,, P. E. Ray,, V. R. Gordeuk, and, S. Nekhai. 2007. Iron chelators ICL670 and 311 inhibit HIV-1 transcription. Virology 367: 324333.
31. DeJong, E. S.,, C. E. Chang,, M. K. Gilson, and, J. P. Marino. 2003. Proflavine acts as a Rev inhibitor by targeting the high-affinity Rev binding site of the Rev responsive element of HIV-1. Biochemistry 42: 80358046.
32. Deng, L.,, T. Ammosova,, A. Pumfery,, F. Kashanchi, and, S. Nekhai. 2002. HIV-1 Tat interaction with RNA polymerase II C-terminal domain (CTD) and a dynamic association with CDK2 induce CTD phosphorylation and transcription from HIV-1 promoter. J. Biol. Chem. 277: 3392233929.
33. Diwan, P.,, J. J. Lacasse, and, L. M. Schang. 2004. Roscovitine inhibits activation of promoters in herpes simplex virus type 1 genomes independently of promoter-specific factors. J. Virol. 78: 93529365.
34. Du, Z.,, K. E. Lind, and, T. L. James. 2002. Structure of TAR RNA complexed with a Tat-TAR interaction nanomolar inhibitor that was identified by computational screening. Chem. Biol. 9: 707712.
35. Fang, J.,, S. Kubota,, B. Yang,, N. Zhou,, H. Zhang,, R. Godbout, and, R. J. Pomerantz. 2004. A DEAD box protein facilitates HIV-1 replication as a cellular co-factor of Rev. Virology 330: 471480.
36. Fineberg, K.,, T. Fineberg,, A. Graessmann,, N. W. Luedtke,, Y. Tor,, R. Lixin,, D. A. Jans, and, A. Loyter. 2003. Inhibition of nuclear import mediated by the Rev-arginine rich motif by RNA molecules. Biochemistry 42: 26252633.
37. Fornerod, M.,, M. Ohno,, M. Yoshida, and, I. W. Mattaj. 1997. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell 90: 10511060.
38. Fraldi, A.,, F. Varrone,, G. Napolitano,, A. A. Michels,, B. Majello,, O. Bensaude, and, L. Lania. 2005. Inhibition of Tat activity by the HEXIM1 protein. Retrovirology 2: 42.
39. Fritz, C. C.,, M. L. Zapp, and, M. R. Green. 1995. A human nucleoporin-like protein that specifically interacts with HIV Rev. Nature 376: 530533.
40. Fujinaga, K.,, D. Irwin,, Y. Huang,, R. Taube,, T. Kurosu, and, B. M. Peterlin. 2004. Dynamics of human immunodeficiency virus transcription: P-TEFb phosphorylates RD and dissociates negative effectors from the transactivation response element. Mol. Cell. Biol. 24: 787795.
41. Gao, J., and, D. R. Richardson. 2001. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents. IV. The mechanisms involved in inhibiting cell-cycle progression. Blood 98: 842850.
42. Grendys, E. C., Jr.,, J. A. Blessing,, R. Burger, and, J. Hoffman. 2005. A phase II evaluation of flavopiridol as second-line chemotherapy of endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol. Oncol. 98: 249253.
43. Haaland, R. E.,, C. H. Herrmann, and, A. P. Rice. 2005. siRNA depletion of 7SK snRNA induces apoptosis but does not affect expression of the HIV-1 LTR or P-TEFb-dependent cellular genes. J. Cell Physiol. 205: 463470.
44. Hamasaki, K., and, A. Ueno. 2001. Aminoglycoside antibiotics, neamine and its derivatives as potent inhibitors for the RNA-protein interactions derived from HIV-1 activators. Bioorg. Med. Chem. Lett. 11: 591594.
45. He, G., and, D. M. Margolis. 2002. Counterregulation of chromatin deacetylation and histone deacetylase occupancy at the integrated promoter of human immunodeficiency virus type 1 (HIV-1) by the HIV-1 repressor YY1 and HIV-1 activator Tat. Mol. Cell. Biol. 22: 29652973.
46. He, M.,, D. Yuan,, W. Lin,, R. Pang,, X. Yu, and, M. Yang. 2005. Synthesis and assay of isoquinoline derivatives as HIV-1 Tat-TAR interaction inhibitors. Bioorg. Med. Chem. Lett. 15: 39783981.
47. Held, D. M.,, J. D. Kissel,, J. T. Patterson,, D. G. Nickens, and, D. H. Burke. 2006. HIV-1 inactivation by nucleic acid aptamers. Front. Biosci. 11: 89112.
48. Henderson, B. R., and, P. Percipalle. 1997. Interactions between HIV Rev and nuclear import and export factors: the Rev nuclear localisation signal mediates specific binding to human importinbeta. J. Mol. Biol. 274: 693707.
49. Heredia, A.,, C. Davis,, D. Bamba,, N. Le,, M. Y. Gwarzo,, M. Sadowska,, R. C. Gallo, and, R. R. Redfield. 2005. Indirubin-3’-monoxime, a derivative of a Chinese antileukemia medicine, inhibits P-TEFb function and HIV-1 replication. AIDS 19: 20872095.
50. Hetzer, C.,, D. Bisgrove,, M. S. Cohen,, A. Pedal,, K. Kaehlcke,, A. Speyerer,, K. Bartscherer,, J. Taunton, and, M. Ott. 2007. Recruitment and activation of RSK2 by HIV-1 Tat. PLoS ONE 2: e151.
51. Hoque, M.,, B. Tian,, M. B. Mathews, and, T. Pe’ery. 2005. Granulin and granulin repeats interact with the Tat.P-TEFb complex and inhibit Tat transactivation. J. Biol. Chem. 280: 1364813657.
52. Hoque, M.,, T. M. Young,, C. G. Lee,, G. Serrero,, M. B. Mathews, and, T. Pe’ery. 2003. The growth factor granulin interacts with cyclin T1 and modulates P-TEFb-dependent transcription. Mol. Cell. Biol. 23: 16881702.
53. Hwang, S.,, N. Tamilarasu,, K. Kibler,, H. Cao,, A. Ali,, Y. H. Ping,, K. T. Jeang, and, T. M. Rana. 2003. Discovery of a small molecule Tat-trans-activation-responsive RNA antagonist that potently inhibits human immunodeficiency virus-1 replication. J. Biol. Chem. 278: 3909239103.
54. Iguchi, T.,, H. Ishikawa,, H. Matumoto,, M. Mizuno,, K. Goto, and, K. Hamasaki. 2005. Amino disaccharides having an alpha-(1→4) or a beta-(1→4) linkage, their synthesis and evaluation as a potential inhibitor for HIV-1 TAR-Tat. Nucleic Acids Symp. Ser. (Oxford) 2005: 169170.
55. Isel, C., and, J. Karn. 1999. Direct evidence that HIV-1 Tat stimulates RNA polymerase II carboxyl-terminal domain hyperphosphorylation during transcriptional elongation. J. Mol. Biol. 290: 929941.
56. Ivanova, G.,, S. Reigadas,, D. Ittig,, A. Arzumanov,, M. L. Andreola,, C. Leumann,, J. J. Toulme, and, M. J. Gait. 2007. Tricyclo-DNA containing oligonucleotides as steric block inhibitors of human immunodeficiency virus type 1 tat-dependent trans-activation and HIV-1 infectivity. Oligonucleotides 17: 5465.
57. Jang, M. K.,, K. Mochizuki,, M. Zhou,, H. S. Jeong,, J. N. Brady, and, K. Ozato. 2005. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol. Cell 19: 523534.
58. Kleymann, G.,, R. Fischer,, U. A. Betz,, M. Hendrix,, W. Bender,, U. Schneider,, G. Handke,, P. Eckenberg,, G. Hewlett,, V. Pevzner,, J. Baumeister,, O. Weber,, K. Henninger,, J. Keldenich,, A. Jensen,, J. Kolb,, U. Bach,, A. Popp,, J. Maben,, I. Frappa,, D. Haebich,, O. Lockhoff, and, H. Rubsamen-Waigmann. 2002. New helicaseprimase inhibitors as drug candidates for the treatment of herpes simplex disease. Nat. Med. 8: 392398.
59. Kouroukis, C. T.,, A. Belch,, M. Crump,, E. Eisenhauer,, R. D. Gascoyne,, R. Meyer,, R. Lohmann,, P. Lopez,, J. Powers,, R. Turner, and, J. M. Connors. 2003. Flavopiridol in untreated or relapsed mantle-cell lymphoma: results of a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 21: 17401745.
60. Kwong, A. D.,, B. G. Rao, and, K. T. Jeang. 2005. Viral and cellular RNA helicases as antiviral targets. Nat. Rev. Drug Discov. 4: 845853.
61. Lassen, K.,, Y. Han,, Y. Zhou,, J. Siliciano, and, R. F. Siliciano. 2004. The multifactorial nature of HIV-1 latency. Trends Mol. Med. 10: 525531.
62. Lee, S. W.,, H. F. Gallardo,, E. Gilboa, and, C. Smith. 1994. Inhibition of human immunodeficiency virus type 1 in human T cells by a potent Rev response element decoy consisting of the 13-nucleotide minimal Rev-binding domain. J. Virol. 68: 82548264.
63. Lehrman, G.,, I. B. Hogue,, S. Palmer,, C. Jennings,, C. A. Spina,, A. Wiegand,, A. L. Landay,, R. W. Coombs,, D. D. Richman,, J. W. Mellors,, J. M. Coffin,, R. J. Bosch, and, D. M. Margolis. 2005. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet 366: 549555.
64. Li, Q.,, J. P. Price,, S. A. Byers,, D. Cheng,, J. Peng, and, D. H. Price. 2005. Analysis of the large inactive P-TEFb complex indicates that it contains one 7SK molecule, a dimer of HEXIM1 or HEXIM2, and two P-TEFb molecules containing Cdk9 phosphorylated at threonine 186. J. Biol. Chem. 280: 2881928826.
65. Liang, Y.,, J. Narayanasamy,, K. L. Rapp,, R. F. Schinazi, and, C. K. Chu. 2006. PAMAM dendrimers and branched polyethyleneglycol (nanoparticles) prodrugs of (-)-beta-D-(2R, 4R)-dioxolanethymine (DOT) and their anti-HIV activity. Antivir. Chem. Che-mother. 17: 321329.
66. Lind, K. E.,, Z. Du,, K. Fujinaga,, B. M. Peterlin, and, T. L. James. 2002. Structure-based computational database screening, in vitro assay, and NMR assessment of compounds that target TAR RNA. Chem. Biol. 9: 185193.
67. Liu, G.,, D. R. Gandara,, P. N. Lara, Jr.,, D. Raghavan,, J. H. Doro-show,, P. Twardowski,, P. Kantoff,, W. Oh,, K. Kim, and, G. Wilding. 2004. A Phase II trial of flavopiridol (NSC #649890) in patients with previously untreated metastatic androgen-independent prostate cancer. Clin. Cancer Res. 10: 924928.
68. Loyer, P.,, J. H. Trembley,, R. Katona,, V. J. Kidd, and, J. M. Lahti. 2005. Role of CDK/cyclin complexes in transcription and RNA splicing. Cell. Signal. 17: 10331051.
69. Luo, Y.,, H. Yu, and, B. M. Peterlin. 1994. Cellular protein modulates effects of human immunodeficiency virus type 1 Rev. J. Virol. 68: 38503856.
70. Marquez, N.,, R. Sancho,, A. Macho,, A. Moure,, I. Masip,, A. Messeguer, and, E. Munoz. 2006. Anti-Tat and anti-HIV activities of trimers of n-alkylglycines. Biochem. Pharmacol. 71: 596604.
71. Michels, A. A.,, V. T. Nguyen,, A. Fraldi,, V. Labas,, M. Edwards,, F. Bonnet,, L. Lania, and, O. Bensaude. 2003. MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcription-dependent manner. Mol. Cell. Biol. 23: 48594869.
72. Mills, N. L.,, A. A. Shelat, and, R. K. Guy. 2007. Assay optimization and screening of RNA-protein interactions by AlphaScreen. J. Biomol. Screen. 12: 946955.
73. Modem, S.,, K. R. Badri,, T. C. Holland, and, T. R. Reddy. 2005. Sam68 is absolutely required for Rev function and HIV-1 production. Nucleic Acids Res. 33: 873879.
74. Molle, D.,, P. Maiuri,, S. Boireau,, E. Bertrand,, A. Knezevich,, A. Marcello, and, E. Basyuk. 2007. A real-time view of the TAR:Tat: P-TEFb complex at HIV-1 transcription sites. Retrovirology 4: 36.
75. Mujtaba, S.,, Y. He,, L. Zeng,, A. Farooq,, J. E. Carlson,, M. Ott,, E. Verdin, and, M. M. Zhou. 2002. Structural basis of lysineacetylated HIV-1 Tat recognition by PCAF bromodomain. Mol. Cell 9: 575586.
76. Murakami, N.,, Y. Ye,, M. Kawanishi,, S. Aoki,, N. Kudo,, M. Yoshida,, E. E. Nakayama,, T. Shioda, and, M. Kobayashi. 2002. New Rev-transport inhibitor with anti-HIV activity from Valerianae Radix. Bioorg. Med. Chem. Lett. 12: 28072810.
77. Nekhai, S.,, U. G. Bhat,, T. Ammosova,, S. K. Radhakrishnan,, M. Jerebtsova,, X. Niu,, A. Foster,, T. J. Layden, and, A. L. Gartel. 2007. A novel anticancer agent ARC antagonizes HIV-1 and HCV. Oncogene 26: 38993903.
78. Nekhai, S., and, K. T. Jeang. 2006. Transcriptional and post-transcriptional regulation of HIV-1 gene expression: role of cellular factors for Tat and Rev. Future Microbiol. 1: 417426.
79. Nekhai, S.,, M. Zhou,, A. Fernandez,, W. S. Lane,, N. J. Lamb,, J. Brady, and, A. Kumar. 2002. HIV-1 Tat-associated RNA polymerase C-terminal domain kinase, CDK2, phosphorylates CDK7 and stimulates Tat-mediated transcription. Biochem. J. 364: 649657.
80. Nguyen, V. T.,, T. Kiss,, A. A. Michels, and, O. Bensaude. 2001. 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature 414: 322325.
81. Nishizono, N., and, V. Nair. 2000. Synthesis of biomimetic analogs of neomycin B: potential inhibitors of the HIV RNA Rev response element. Nucleosides Nucleotides Nucleic Acids 19: 283295.
82. Okamoto, H.,, T. P. Cujec,, M. Okamoto,, B. M. Peterlin,, M. Baba, and, T. Okamoto. 2000. Inhibition of the RNA-dependent trans-activation and replication of human immunodeficiency virus type 1 by a fluoroquinoline derivative K-37. Virology 272: 402408.
83. Pagans, S.,, A. Pedal,, B. J. North,, K. Kaehlcke,, B. L. Marshall,, A. Dorr,, C. Hetzer-Egger,, P. Henklein,, R. Frye,, M. W. McBurney,, H. Hruby,, M. Jung,, E. Verdin, and, M. Ott. 2005. SIRT1 regulates HIV transcription via Tat deacetylation. PLoS Biol. 3: e41.
84. Pan, C.,, M. Mezei,, S. Mujtaba,, M. Muller,, L. Zeng,, J. Li,, Z. Wang, and, M. M. Zhou. 2007. Structure-guided optimization of small molecules inhibiting human immunodeficiency virus 1 Tat association with the human coactivator p300/CREB binding protein-associated factor. J. Med. Chem. 50: 22852288.
85. Parolin, C.,, B. Gatto,, C. Del Vecchio,, T. Pecere,, E. Tramontano,, V. Cecchetti,, A. Fravolini,, S. Masiero,, M. Palumbo, and, G. Palu. 2003. New anti-human immunodeficiency virus type 1 6-amino-quinolones: mechanism of action. Antimicrob. Agents Chemother. 47: 889896.
86. Pollard, V. W., and, M. H. Malim. 1998. The HIV-1 Rev protein. Annu. Rev. Microbiol. 52: 491532.
87. Porter, J. B. 2006. Deferasirox: an effective once-daily orally active iron chelator. Drugs Today(Barcelona) 42: 623637.
88. Prelich, G. 2002. RNA polymerase II carboxy-terminal domain kinases: emerging clues to their function. Eukaryot. Cell 1: 153162.
89. Radhakrishnan, S. K., and, A. L. Gartel. 2006. A novel transcriptional inhibitor induces apoptosis in tumor cells and exhibits anti-angiogenic activity. Cancer Res. 66: 32643270.
90. Renner, S.,, V. Ludwig,, O. Boden,, U. Scheffer,, M. Gobel, and, G. Schneider. 2005. New inhibitors of the Tat-TAR RNA interaction found with a “fuzzy” pharmacophore model. Chembiochem 6: 11191125.
91. Richter, S.,, C. Parolin,, B. Gatto,, C. Del Vecchio,, E. BroccaCofano,, A. Fravolini,, G. Palu, and, M. Palumbo. 2004. Inhibition of human immunodeficiency virus type 1 Tat- trans-activation-responsive region interaction by an antiviral quinolone derivative. Antimicrob. Agents Chemother. 48: 18951899.
92. Rosorius, O.,, B. Reichart,, F. Kratzer,, P. Heger,, M. C. Dabauvalle, and, J. Hauber. 1999. Nuclear pore localization and nucleocytoplasmic transport of eIF-5A: evidence for direct interaction with the export receptor CRM1. J. Cell Sci. 112 (Pt. 14): 23692380.
93. Ruhl, M.,, M. Himmelspach,, G. M. Bahr,, F. Hammerschmid,, H. Jaksche,, B. Wolff,, H. Aschauer,, G. K. Farrington,, H. Probst,, D. Bevec, et al. 1993. Eukaryotic initiation factor 5A is a cellular target of the human immunodeficiency virus type 1 Rev activation domain mediating trans-activation. J. Cell Biol. 123: 13091320.
94. Salerno, D.,, M. G. Hasham,, R. Marshall,, J. Garriga,, A. Y. Tsygankov, and, X. Grana. 2007. Direct inhibition of CDK9 blocks HIV-1 replication without preventing T-cell activation in primary human peripheral blood lymphocytes. Gene 405: 6578.
95. Sanchez, V.,, A. K. McElroy,, J. Yen,, S. Tamrakar,, C. L. Clark,, R. A. Schwartz, and, D. H. Spector. 2004. Cyclin-dependent kinase activity is required at early times for accurate processing and accumulation of the human cytomegalovirus UL122–123 and UL37 immediate-early transcripts and at later times for virus production. J. Virol. 78: 1121911232.
96. Sanchez-Velar, N.,, E. B. Udofia,, Z. Yu, and, M. L. Zapp. 2004. hRIP, a cellular cofactor for Rev function, promotes release of HIV RNAs from the perinuclear region. Genes Dev. 18: 2334.
97. Savarino, A.,, M. Pistello,, D. D’Ostilio,, E. Zabogli,, F. Taglia,, F. Mancini,, S. Ferro,, D. Matteucci,, L. De Luca,, M. L. Barreca,, A. Ciervo,, A. Chimirri,, M. Ciccozzi, and, M. Bendinelli. 2007. Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication in vitro and provide a rationale to redesign antiretroviral treatment for feline AIDS. Retrovirology 4: 79.
98. Schmitt, C.,, C. von Kobbe,, A. Bachi,, N. Pante,, J. P. Rodrigues,, C. Boscheron,, G. Rigaut,, M. Wilm,, B. Seraphin,, M. CarmoFonseca, and, E. Izaurralde. 1999. Dbp5, a DEAD-box protein required for mRNA export, is recruited to the cytoplasmic fibrils of nuclear pore complex via a conserved interaction with CAN/ Nup159p. EMBO J. 18: 43324347.
99. Schulte, A.,, N. Czudnochowski,, M. Barboric,, A. Schonichen,, D. Blazek,, B. M. Peterlin, and, M. Geyer. 2005. Identification of a cyclin T-binding domain in Hexim1 and biochemical analysis of its binding competition with HIV-1 Tat. J. Biol. Chem. 280: 2496824977.
100. Shapiro, G. I.,, J. G. Supko,, A. Patterson,, C. Lynch,, J. Lucca,, P. F. Zacarola,, A. Muzikansky,, J. J. Wright,, T. J. Lynch, Jr., and, B. J. Rollins. 2001. A phase II trial of the cyclin-dependent kinase inhibitor flavopiridol in patients with previously untreated stage IV non-small cell lung cancer. Clin. Cancer Res. 7: 15901599.
101. Sharma, M.,, A. A. George,, B. N. Singh,, N. C. Sahoo, and, K. V. Rao. 2007. Regulation of transcript elongation through cooperative and ordered recruitment of cofactors. J. Biol. Chem. 282: 2088720896.
102. Shima, D.,, M. Yugami,, M. Tatsuno,, T. Wada,, Y. Yamaguchi, and, H. Handa. 2003. Mechanism of H-8 inhibition of cyclin-dependent kinase 9: study using inhibitor-immobilized matrices. Genes Cells 8: 215223.
103. Shimizu, S.,, E. Urano,, Y. Futahashi,, K. Miyauchi,, M. Isogai,, Z. Matsuda,, K. Nohtomi,, T. Onogi,, Y. Takebe,, N. Yamamoto, and, J. Komano. 2007. Inhibiting lentiviral replication by HEXIM1, a cellular negative regulator of the CDK9/cyclin T complex. AIDS 21: 575582.
104. Shimura, K.,, E. Kodama,, Y. Sakagami,, Y. Matsuzaki,, W. Watanabe,, K. Yamataka,, Y. Watanabe,, Y. Ohata,, S. Doi,, M. Sato,, M. Kano,, S. Ikeda, and, M. Matsuoka. 2008. Broad anti-retroviral activity and resistance profile of a novel human immunodeficiency virus integrase inhibitor, elvitegravir (JTK-303/GS-9137). J. Virol. 82: 764774.
105. Stevens, M.,, J. Balzarini,, I. M. Lagoja,, B. Noppen,, K. Francois,, A. Van Aerschot,, P. Herdewijn,, E. De Clercq, and, C. Pannecouque. 2007. Inhibition of human immunodeficiency virus type 1 transcription by N-aminoimidazole derivatives. Virology 365: 220237.
106. Symensma, T. L.,, S. Baskerville,, A. Yan, and, A. D. Ellington. 1999. Polyvalent Rev decoys act as artificial Rev-responsive elements. J. Virol. 73: 43414349.
107. Szebeni, A.,, B. Mehrotra,, A. Baumann,, S. A. Adam,, P. T. Wing-field, and, M. O. Olson. 1997. Nucleolar protein B23 stimulates nuclear import of the HIV-1 Rev protein and NLS-conjugated albumin. Biochemistry 36: 39413949.
108. Theisen, D. M.,, C. Pongratz,, K. Wiegmann,, F. Rivero,, O. Krut, and, M. Kronke. 2006. Targeting of HIV-1 Tat traffic and function by transduction-competent single chain antibodies. Vaccine 24: 31273136.
109. Traore, H. N., and, D. Meyer. 2004. The effect of iron overload on in vitro HIV-1 infection. J. Clin. Virol. 31 (Suppl. 1): S92S98.
110. Tripathi, S.,, B. Chaubey,, S. Ganguly,, D. Harris,, R. A. Casale, and, V. N. Pandey. 2005. Anti-HIV-1 activity of anti-TAR poly-amide nucleic acid conjugated with various membrane transducing peptides. Nucleic Acids Res. 33: 43454356.
111. Turano, M.,, G. Napolitano,, C. Dulac,, B. Majello,, O. Bensaude, and, L. Lania. 2006. Increased HEXIM1 expression during erythroleukemia and neuroblastoma cell differentiation. J. Cell. Physiol. 206: 603610.
112. Turner, J. J.,, G. D. Ivanova,, B. Verbeure,, D. Williams,, A. A. Arzumanov,, S. Abes,, B. Lebleu, and, M. J. Gait. 2005. Cell-penetrating peptide conjugates of peptide nucleic acids (PNA) as inhibitors of HIV-1 Tat-dependent trans-activation in cells. Nucleic Acids Res. 33: 68376849.
113. Van Veldhuizen, P. J.,, J. R. Faulkner,, P. N. Lara, Jr.,, P. H. Gumer-lock,, J. W. Goodwin,, S. R. Dakhil,, H. M. Gross,, R. C. Flanigan, and, E. D. Crawford. 2005. A phase II study of flavopiridol in patients with advanced renal cell carcinoma: results of Southwest Oncology Group Trial 0109. Cancer Chemother. Pharmacol. 56: 3945.
114. Wang, H. K. 2001. Flavopiridol. National Cancer Institute. Curr. Opin. Investig. Drugs 2: 11491155.
115. Wang, M.,, Z. Xu,, P. Tu,, X. Yu,, S. Xiao, and, M. Yang. 2004. Alpha,alpha-trehalose derivatives bearing guanidino groups as inhibitors to HIV-1 Tat-TAR RNA interaction in human cells. Bioorg. Med. Chem. Lett. 14: 25852588.
116. Wang, W.,, Z. Guo,, Y. Chen,, T. Liu, and, L. Jiang. 2006. Influence of generation 2-5 of PAMAM dendrimer on the inhibition of Tat peptide/TAR RNA binding in HIV-1 transcription. Chem. Biol. Drug. Des. 68: 314318.
117. Wang, X.,, K. Yamataka,, M. Okamoto,, S. Ikeda, and, M. Baba. 2007. Potent and selective inhibition of Tat-dependent HIV-1 replication in chronically infected cells by a novel naphthalene derivative JTK-101. Antivir. Chem. Chemother. 18: 201211.
118. Wei, P.,, M. E. Garber,, S. M. Fang,, W. H. Fischer, and, K. A. Jones. 1998. A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA. Cell 92: 451462.
119. Wolff, B.,, J. J. Sanglier, and, Y. Wang. 1997. Leptomycin B is an inhibitor of nuclear export: inhibition of nucleo-cytoplasmic trans-location of the human immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent mRNA. Chem. Biol. 4: 139147.
120. Xiao, G.,, A. Kumar,, K. Li,, C. T. Rigl,, M. Bajic,, T. M. Davis,, D. W. Boykin, and, W. D. Wilson. 2001. Inhibition of the HIV-1 rev-RRE complex formation by unfused aromatic cations. Bioorg. Med. Chem. 9: 10971113.
121. Yang, Z.,, J. H. Yik,, R. Chen,, N. He,, M. K. Jang,, K. Ozato, and, Q. Zhou. 2005. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol. Cell 19: 535545.
122. Yang, Z.,, Q. Zhu,, K. Luo, and, Q. Zhou. 2001. The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature 414: 317322.
123. Yedavalli, V. S.,, C. Neuveut,, Y. H. Chi,, L. Kleiman, and, K. T. Jeang. 2004. Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function. Cell 119: 381392.
124. Yik, J. H.,, R. Chen,, R. Nishimura,, J. L. Jennings,, A. J. Link, and, Q. Zhou. 2003. Inhibition of P-TEFb (CDK9/Cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA. Mol. Cell 12: 971982.
125. Yuan, D.,, M. He,, R. Pang,, S. S. Lin,, Z. Li, and, M. Yang. 2007. The design, synthesis, and biological evaluation of novel substituted purines as HIV-1 Tat-TAR inhibitors. Bioorg. Med. Chem. 15: 265272.
126. Zapp, M. L.,, S. Stern, and, M. R. Green. 1993. Small molecules that selectively block RNA binding of HIV-1 Rev protein inhibit Rev function and viral production. Cell 74: 969978.
127. Zapp, M. L.,, D. W. Young,, A. Kumar,, R. Singh,, D. W. Boykin,, W. D. Wilson, and, M. R. Green. 1997. Modulation of the RevRRE interaction by aromatic heterocyclic compounds. Bioorg. Med. Chem. 5: 11491155.
128. Zeng, L.,, J. Li,, M. Muller,, S. Yan,, S. Mujtaba,, C. Pan,, Z. Wang, and, M. M. Zhou. 2005. Selective small molecules blocking HIV-1 Tat and coactivator PCAF association. J. Am. Chem. Soc. 127: 23762377.
129. Zhang, N.,, H. M. Chen,, V. Koch,, H. Schmitz,, C. L. Liao,, M. Bretner,, V. S. Bhadti,, A. I. Fattom,, R. B. Naso,, R. S. Hos-mane, and, P. Borowski. 2003. Ring-expanded (“fat”) nucleoside and nucleotide analogues exhibit potent in vitro activity against flaviviridae NTPases/helicases, including those of the West Nile virus, hepatitis C virus, and Japanese encephalitis virus. J. Med. Chem. 46: 41494164.
130. Zhang, N.,, H. M. Chen,, V. Koch,, H. Schmitz,, M. Minczuk,, P. Stepien,, A. I. Fattom,, R. B. Naso,, K. Kalicharran,, P. Borowski, and, R. S. Hosmane. 2003. Potent inhibition of NTPase/helicase of the West Nile virus by ring-expanded (“fat”) nucleoside analogues. J. Med. Chem. 46: 776789.
131. Zhou, M.,, H. Lu,, H. Park,, J. Wilson-Chiru,, R. Linton, and, J. N. Brady. 2006. Tax interacts with P-TEFb in a novel manner to stimulate human T-lymphotropic virus type 1 transcription. J. Virol. 80: 47814791.


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Table 1.

Small-molecule inhibitors of Tat-TAR RNA interaction

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6
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Table 2.

Inhibitors of CDK9, cyclin T1, and CDK2

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6
Generic image for table
Table 3.

Inhibitors of Tat-binding cofactors

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6
Generic image for table
Table 4.

Cellular proteins proposed to interact directly with Rev

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6
Generic image for table
Table 5.

Selected inhibitors of Rev function

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6

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