Rev响应元件

人類免疫缺乏病毒的Rev响应元件（英語：Rev response element，RRE）是一个高度结构化的长约350核苷酸的RNA片段，位于病毒基因Env的蛋白编码区内部。在HIV-1的辅助蛋白Rev存在的情况下，带有RRE的HIV-1mRNA会从细胞核输出到細胞質中，参与进一步的翻译与病毒包装。 HIV-1病毒基因组包括单个启动子和多个开放阅读框，并可以通过前mRNA的可变剪切编码15种蛋白质。整合到宿主基因组中的HIV-1原病毒会转录一个长9kb 的前mRNA（pre-mRNA）带有多个剪切位点和核滞留信号。在病毒循环的早期，这一前mRNA会完全剪切为不带Rev响应元件的2kb片段。这些片段能通过标准的mRNA出核途径运出细胞核进入细胞质（见右图上部），这些2kb小mRNA中的一个能编码HIV-1的Rev蛋白，Rev蛋白再通过其核定位信号再进入细胞核。这一期也被称为病毒循环的Rev/RRE不依赖期。 在病毒循环的晚期，Rev 蛋白会进入细胞核并结合在新转录生成 9kb 病毒RNA（未经剪接）或4kb RNA（经过剪接）的 RRE区域上（见右图下部），并帮助其输出到细胞质。这些RNA会翻译为HIV的晚期蛋白质，其中9kb RNA会包装为新的病毒。 Cullen, Bryan R. Nuclear mRNA export: Insights from virology. Trends in Biochemical Sciences. 2003, 28 (8): 419–24. PMID 12932730. doi:10.1016/S0968-0004(03)00142-7.  Pollard, Victoria W.; Malim, Michael H. The Hiv-1 Rev Protein. Annual Review of Microbiology. 1998, 52: 491–532. PMID 9891806. doi:10.1146/annurev.micro.52.1.491.  Frankel, Alan D.; Young, John A. T. HIV-1: Fifteen Proteins and an RNA. Annual Review of Biochemistry. 1998, 67: 1–25. PMID 9759480. doi:10.1146/annurev.biochem.67.1.1.  Cullen, Bryan R. Human immunodeficiency virus: Nuclear RNA export unwound. Nature. 2005, 433 (7021): 26–7. PMID 15635396. doi:10.1038/433026a.  Daugherty, Matthew D; Liu, Bella; Frankel, Alan D. Structural basis for cooperative RNA binding and export complex assembly by HIV Rev. Nature Structural & Molecular Biology. 2010, 17 (11): 1337–42. PMC 2988976 . PMID 20953181. doi:10.1038/nsmb.1902.  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. Proceedings of the National Academy of Sciences. 2010, 107 (28): 12481–6. PMC 2906596 . PMID 20616058. doi:10.1073/pnas.1007022107.  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. Proceedings of the National Academy of Sciences. 2010, 107 (13): 5810–4. PMC 2851902 . PMID 20231488. doi:10.1073/pnas.0914946107.  Legiewicz, M.; Badorrek, C. S.; Turner, K. B.; Fabris, D.; Hamm, T. E.; Rekosh, D.; Hammarskjold, M.-L.; Le Grice, S. F. J. Resistance to RevM10 inhibition reflects a conformational switch in the HIV-1 Rev response element. Proceedings of the National Academy of Sciences. 2008, 105 (38): 14365–70. PMC 2567145 . PMID 18776047. doi:10.1073/pnas.0804461105.  Srinivasakumar, Narasimhachar. Substitution of the Rev-response element in an HIV-1-based gene delivery system with that of SIVmac239 allows efficient delivery of Rev M10 into T-lymphocytes. AIDS Research and Therapy. 2008, 5: 11. PMC 2438438 . PMID 18534033. doi:10.1186/1742-6405-5-11.  Sugaya, Maki; Nishino, Norikazu; Katoh, Akira; Harada, Kazuo. Amino acid requirement for the high affinity binding of a selected arginine-rich peptide with the HIV Rev-response element RNA. Journal of Peptide Science. 2008, 14 (8): 924–35. PMID 18351707. doi:10.1002/psc.1027.  Moehle, Kerstin; Athanassiou, Zafiria; Patora, Krystyna; Davidson, Amy; Varani, Gabriele; Robinson, John A. Design of β-Hairpin Peptidomimetics That Inhibit Binding of α-Helical HIV-1 Rev Protein to the Rev Response Element RNA. Angewandte Chemie International Edition. 2007, 46 (47): 9101–4. doi:10.1002/anie.200702801.  Prater, Chrissy E.; Saleh, Anthony D.; Wear, Maggie P.; Miller, Paul S. Chimeric RNase H-competent oligonucleotides directed to the HIV-1 Rev response element. Bioorganic & Medicinal Chemistry. 2007, 15 (16): 5386–95. PMC 1987364 . PMID 17566743. doi:10.1016/j.bmc.2007.05.066.  Phuphuakrat, Angsana; Auewarakul, Prasert. Functional Variability of Rev Response Element in HIV-1 Primary Isolates. Virus Genes. 2005, 30 (1): 23–9. PMID 15744559. doi:10.1007/s11262-004-4578-9.  Phuphuakrat, Angsana; Paris, Robert M.; Nittayaphan, Sorachai; Louisirirotchanakul, Suda; Auewarakul, Prasert. Functional variation of HIV-1 Rev response element in a longitudinally studied cohort. Journal of Medical Virology. 2005, 75 (3): 367–73. PMID 15648073. doi:10.1002/jmv.20279.  Luedtke, Nathan W.; Liu, Qi; Tor, Yitzhak. RNA−Ligand Interactions: Affinity and Specificity of Aminoglycoside Dimers and Acridine Conjugates to the HIV-1 Rev Response Element†. Biochemistry. 2003, 42 (39): 11391–403. PMID 14516190. doi:10.1021/bi034766y.  Phuphuakrat, Angsana; Auewarakul, Prasert. Heterogeneity of HIV-1 Rev Response Element. AIDS Research and Human Retroviruses. 2003, 19 (7): 569–74. PMID 12908934. doi:10.1089/088922203322230932.  Chapman, Richard L.; Stanley, Thomas B.; Hazen, Richard; Garvey, Edward P. Small molecule modulators of HIV Rev/Rev response element interaction identified by random screening. Antiviral Research. 2002, 54 (3): 149–62. PMID 12062388. doi:10.1016/S0166-3542(01)00222-4.  Nishizono, Naozumi; Nair, Vasu. Synthesis of Biomimetic Analogs of Neomycin B: Potential Inhibitors of the HIV RNA Rev Response Element. Nucleosides, Nucleotides and Nucleic Acids. 2000, 19: 283–95. doi:10.1080/15257770008033010.  Van Ryk, D. I.; Venkatesan, S. Real-time Kinetics of HIV-1 Rev-Rev Response Element Interactions. DEFINITION OF MINIMAL BINDING SITES ON RNA AND PROTEIN AND STOICHIOMETRIC ANALYSIS. Journal of Biological Chemistry. 1999, 274 (25): 17452–63. PMID 10364175. doi:10.1074/jbc.274.25.17452.  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. Proceedings of the National Academy of Sciences. 1997, 94 (3): 973–8. PMC 19624 . PMID 9023367. doi:10.1073/pnas.94.3.973.  Yamada, O; Kraus, G; Luznik, L; Yu, M; Wong-Staal, F. A chimeric human immunodeficiency virus type 1 (HIV-1) minimal Rev response element-ribozyme molecule exhibits dual antiviral function and inhibits cell-cell transmission of HIV-1. Journal of Virology. 1996, 70 (3): 1596–601. PMC 189982 . PMID 8627679.  Dandekar, T; Koch, G. DNA and mRNA sequence of the immune protective DNA ligase I gene match the rev response element of HIV. DNA sequence. 1996, 6 (2): 119–21. PMID 8907308. doi:10.3109/10425179609010198.  Williamson, JR; Battiste, JL; Mao, H; Frankel, AD. Interaction of HIV Rev peptides with the Rev response element RNA. Nucleic acids symposium series. 1995, (33): 46–8. PMID 8643394.  Bevec, Dorian; Volc-Platzer, Beatrix; Zimmermann, Klaus; Dobrovnik, Marika; Hauber, Joachim; Veres, Gabor; Böhnlein, Ernst. Constitutive Expression of ChimericNeo-Rev Response Element Transcripts Suppresses HIV-1 Replication in Human CD4+T Lymphocytes. Human Gene Therapy. 1994, 5 (2): 193–201. PMID 8186299. doi:10.1089/hum.1994.5.2-193.  Cohli, H; Fan, B; Joshi, RL; Ramezani, A; Li, X; Joshi, S. Inhibition of HIV-1 multiplication in a human CD4+ lymphocytic cell line expressing antisense and sense RNA molecules containing HIV-1 packaging signal and Rev response element(s). Antisense research and development. 1994, 4 (1): 19–26. PMID 7914762.  Kawamura, Meiko; Katahira, Jun; Fukasawa, Masashi; Sakuragi, Jun-Ichi; Ishikawa, Koh-Ichi; Nakai, Masuyo; Mingle, Julius A.A.; Osei-Kwasi, Mubarak; et al. Isolation and characterization of a highly divergent HIV-2[GH-2]: Generation of an infectious molecular clone and functional analysis of its rev-responsive element in response to primate retrovirus transactivators (rev and rex). Virology. 1992, 188 (2): 850–3. PMID 1585652. doi:10.1016/0042-6822(92)90540-6.  Zimmermann, Klaus; Weber, Sabine; Dobrovnik, Marika; Hauber, Joachim; Böhnlein, Ernst. Expression of Chimeric Neo-Rev Response Element Sequences Interferes with Rev-Dependent HIV-1 Gag Expression. Human Gene Therapy. 1992, 3 (2): 155–61. PMID 1391035. doi:10.1089/hum.1992.3.2-155.  Vaishnav, YN; Vaishnav, M; Wong-Staal, F. Identification and characterization of a nuclear factor that specifically binds to the Rev response element (RRE) of human immunodeficiency virus type 1 (HIV-1). The New biologist. 1991, 3 (2): 142–50. PMID 2065010.  Heaphy, Shaun; Dingwall, Colin; Ernberg, Ingemar; Gait, Michaet J.; Green, Sheila M.; Kern, Jonathan; Lowe, Anthony D.; Singh, Mohinder; Skinner, Michael 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 (4): 685–93. PMID 1689218. doi:10.1016/0092-8674(90)90671-Z.  http://www.scripps.edu/mb/millar/research/rev.htm[失效連結]