抗HIV-1基因治疗新进展

doi:10.3969/j.issn.1006-7795.2014.01.022

摘要/Abstract

摘要：

虽然高效抗反转录病毒治疗（highly active anti-retroviral therapy，HAART）取得了显著的成果，但是抗人类免疫缺陷病毒（human immunodeficiency virus，HIV）药物治疗仍有其局限性（如引起毒素蓄积和病毒突变）。基因治疗在理论上具有较好的抗HIV能力，可以通过持续干扰病毒复制，提供了阻止HIV进行性感染的希望。本篇综述主要探讨当前多种基因治疗策略及其最新进展。

关键词: 获得性免疫缺陷综合征, 人类免疫缺陷病毒1型, 基因疗法, 慢病毒载体

Abstract:

Highly active antiretroviral therapy (HAART) has achieved significant success, but anti-HIV drug treatment still has its limitation,such as causing drug toxicity and viral-escape mutants. Gene therapy has better ability of anti-HIV in theory. It offers the promise of preventing progressive HIV infection by sustained interference with viral replication. Gene-targeting strategies are being developed with RNA-based agents, such as ribozyme, antisense, RNA aptamers and small interfering RNA, and protein-based agents, such as the mutant HIV Rev protein M10, fusion inhibitors and zinc-finger nucleases. This review mainly discusses the various gene therapy strategies and recent progress. Many of these strategies are being tested in ongoing and planned clinical trials.

Key words: acquired immune deficiency syndrome (AIDS), human immunodeficiency virus type 1(HIV-1), gene therapy, lentivector

中图分类号:

R512.91

田雅茹, 焦艳梅, 张彤, 吴昊. 抗HIV-1基因治疗新进展[J]. 首都医科大学学报, 2014, 35(1): 101-107.

Tian Yaru, Jiao Yanmei, Zhang Tong, Wu Hao. Recent progress in the gene therapies against HIV-1[J]. Journal of Capital Medical University, 2014, 35(1): 101-107.

参考文献

[1] Kitahata M M, Gange S J, Abraham A G, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival[J].N Engl J Med,2009,360(18):1815-1826.

[2] Richman D D,Margolis D M,Delaney M,et al. The challenge of finding a cure for HIV Infection [J].Science,2009,323(5919):1304-1307.

[3] Lekakis J, Ikonomidis I. Cardiovascular complications of AIDS[J].Curr Opin Crit Care,2010, 16(5):408-412.

[4] Nunez M. Clinical syndromes and consequences of antiretroviral-related hepatotoxicity [J].Hepatology,2010,52(3):1143-1155.

[5] Xia C, Luo D, Yu X,et al. HIV-associated dementia in the era of highly active antiretroviral therapy (HAART)[J].Microbes Infect,2011, 13(5): 419-425.

[6] Dinoso J B, Kim S Y, Wiegand A M,et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy[J].Proc Natl Acad Sci USA,2009,106(23):9403-9408.

[7] Levine B L, Humeau L M, Boyer J,et al.Gene transfer in humans using a conditionally replicating lentiviral vector[J]. Proc Natl Acad Sci,2006,103(46):17372-17377.

[8] Tebas P, Stein D,Binder-Scholl G, et al.Antiviral effects of autologous CD4 T cells genetically modified with a conditionally replicating lentiviral vector expressing long antisense to HIV[J].Blood,2013,121(9):1524-1533.

[9] Carthew R W,Sontheimer E J. Origins and mechanisms of miRNAs and siRNAs[J]. Cell,2009, 136(4): 642-655.

[10] Nathans R,Chu C Y,Serquina A K,et al.Cellular microRNA and P bodies modulate host-HIV-1 interactions [J].Mol Cell,2009,34(6):696-709.

[11] Sung T L,Rice A P.miR-198 inhibits HIV-1 gene expression and replication in monocytes andits mechanism of action appears to involve repression of Cyclin T1[J].PLoS Pathog, 2009,5(1):e1000263.

[12] Liu Y P,Haasnoot J,ter Brake O,et al.Inhibition of HIV-1 by multiple siRNAs expressed from a single microRNA polycistron[J].Nucleic Acids Res,2008,36(9):2811-2824.

[13] Aagaard L A, Zhang J,von Eije K J, et al. Engineering and optimization of the miR-106b cluster for ectopic expression of multiplexed anti-HIV RNAs [J].Gene Ther,2008,15(23):1536-1549.

[14] Angaji S A, Hedayati S S, Poor R H, et al.Application of RNA interference in treating human diseases[J].J Genet,2010,89(4):527-537.

[15] Tsygankov A Y. Current developments in anti-HIV/AIDS gene therapy[J]. Curr Opin Investig Drugs,2009,10(2):137-149.

[16] Chan J K, Greene W C. Dynamic roles for NF-κB in HTLV-I and HIV-1 retroviral pathogenesis [J].Immunol Rev, 2012, 246(1):286-310.

[17] Shah P S, Pham N P, Schaffer D V. HIV develops indirect crossresistance to combinatorial RNAi targeting two distinct and spatially distant sites[J].Mol Ther, 2012, 20(4):840-848.[JP]

[18] Friedrich B M, Dziuba N, Li G, et al. Host factors mediating HIV-1 replication[J].Virus Res, 2011, 161(2):101-114.[JP]

[19] Eekels J J, Sagnier S, Geerts D, et al. Inhibition of HIV-1 replication with stable RNAi-mediated knockdown of autophagy factors[J].Virol J, 2012, 9:69.

[20] Berkhout B, Sanders R W. Molecular strategies to design an escape-proof antiviral therapy[J].Antiviral Res,2011,92(1):7-14.

[21] Ehsani A,Saetrom P,Zhang J,et al.Rational design of micro-RNA-like bifunctional siRNAs targeting HIV and the HIV coreceptor CCR5[J].Mol Ther,2010,18(4): 796-802.[JP]

[22] Shimizu S, Hong P, Arumugam B,et al.A highly efficient short hairpin RNA potently down-regulates CCR5 expression in systemic lymphoid organs in the hu-BLT mouse model[J].Blood,2010,115(8):1534-1544.

[23] von Eije K J, ter Brake O, Berkhout B. Stringent testing identifies highly potent and escape-proof anti-HIV short hairpin RNAs[J].J Gene Med,2009,11(6): 459-467.

[24] ter Brake O,'t Hooft K, Liu Y P,et al.Lentiviral vector design for multiple shRNA expression and durable HIV-1 inhibition[J].Mol Ther,2008,16(3): 557-564.

[25] Kiem H P, Wu R A, Sun G, et al.Foamy combinatorial anti-HIV vectors with MGMTP140K potently inhibit HIV-1 and SHIV replication and mediate selection in vivo[J].Gene Ther,2010,17(1):37-49.

[26] Liang M, Kamata M, Chen K N,et al.Inhibition of HIV-1 infection by a unique short hairpin RNA to chemokine receptor 5 delivered into macrophages through hematopoietic progenitor cell transduction[J].J Gene Med,2010,12(3):255-265.

[27] Jackson A I,Linsley P S.Recognizing and avoiding siRNA offtarget effects for target identification and therapeutic application[J].Nat Rev Drug Discov,2010,9(1): 57-67.

[28] Reischl D,Zimmer A. Drug delivery of siRNA therapeutics: potentials and limits of nanosystems[J].Nanomedicine,2009,5(1):8-20.

[29] Mulhbacher J, St-Pierre P, Lafontaine D A. Therapeutic applications of ribozymes and riboswitches[J].Curr Opin Pharmacol,2010,10(5): 551-556.

[30] Scarborough J,Lévesque D,Didierlaurent L,et al. In vitro and in vivo cleavage of HIV-1 RNA by new SOFA-HDV ribozymes and their potential to inhibit viral replication[J].RNA Biol,2011,8(2): 343-353.

[31] Mitsuyasu R T, Merigan T C, Carr A, et al. Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34⁺ cells[J].Nat Med,2009,15(3):285-292.

[32] Unwalla H J,Li H T,Li S Y,et al.Use of a U16 snoRNA containing ribozyme library to identify ribozyme targets in HIV-1[J].Mol Ther,2008,16(6): 1113-1119.

[33] Nazari R, Ma X Z, Joshi S. Inhibition of human immunodeficiency virus-1 entry using vectors expressing a multimeric hammerhead ribozyme targeting the CCR5 mRNA[J].J Gen Virol,2008, 89(Pt9): 2252-2261.

[34] DiGiusto D L, Krishnan A, Li L, et al.RNA-based gene therapy for HIV with lentiviral vector–modified CD34⁺cells in patients undergoing transplantation for AIDSrelated lymphoma[J].Sci Transl Med,2010,2(36): 36-43.

[35] Zhou J, Rossi J J. Aptamer-targeted RNAi for HIV-1 therapy[J].Methods Mol Biol, 2011, 721 : 355-371.

[36] Hang J C, Sun L, Nie Q H,et al.Downregulation of CXCR4 expression by SDF-KDEL in CD34⁺ hematopoietic stem cells: an anti-human immunodeficiency virus strategy[J].J Virol Methods,2009,161(1):30-37.

[37] Bai X, Wilson K L, Seedorff J E,et al.Impact of the enfuvirtide resistance mutation N43D and the associated baseline polymorphism E137K on peptide sensitivity and six-helix bundle structure [J]. Biochemistry,2008,47(25): 6662-6670.[JP]

[38] Kimpel J, Braun S E, Qiu G,et al.Survival of the fittest: positive selection of CD4⁺ T cells expressing a membrane-bound fusion inhibitor following HIV-1 infection[J].PLoS One,2010,5 (8): 378-384.

[39] Trobridge G D,Wu R A, Beard B C,et al.Protection of stem cell derived lymphocytes in a primate AIDS gene therapy model after in vivo selection[J].2009. PLoS One 4(11): e7693.

[40] He Y X, Xiao Y H, Song H F, et al.Design and evaluation of sifuvirtide, a novel HIV-1 fusion inhibitor[J].J Biol Chem,2008,283(17):11126-11134.

[41] Urnov F D, Rebar E J, Holmes M C, et al.Genome editing with engineered zinc finger nucleases[J].Nat Rev Genet,2010,11(9):636-646.

[42] Perez E E, Wang J, Miller J C, et al.Establishment of HIV-1 resistance in CD4⁺ T cells by genome editing using zinc-finger nucleases[J].Nat Biotechnol,2008,26(7):808-816.[JP]

[43] Holt N, Wang J, Kim K, et al.Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo[J].Nat Biotechnol,2010,28(8):839-847.

[44] Schopman N C, ter Brake O, Berkhout B. Anticipating and blocking HIV-1 escape by second generation antiviral shRNAs[J].Retrovirology,2010,7:52.

[45] Anderson J S, Javien J, Nolta J A,et al.Preintegration HIV-1 inhibition by a combination lentiviral vector containing a chimeric TRIM5 alpha protein, a CCR5 shRNA, and a TAR decoy[J].Mol Ther,2009,17(12):2103-2114.

[46] Eguchi A,Meade B R,Chang Y C,et al. Efficient siRNA delivery into primary cells by a peptide[J].Nat Biotechnol,2009,27(6): 567-571.

[47] Christie R J,Nishiyama N,Kataoka K.Delivering the code: polyplex carriers for deoxyribonucleic acid and ribonucleic acid interference therapies[J].Eninology,2010,151 (2): 466-473.

[48] Neves J D,Amiji M M, Bahia M F,et al.Nanotechnology-based systems for the treatment and onprevention of HIV/AIDS[J].Adv Drug Deliver Rev,2010,62(4-5): 458-477.[JP]

[49] Biffi A,Bartolomae C C,Cesana D,et al.Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection[J].Blood,2011,117(20): 5332-5339.

[50] Hrecka K, Hao C L, Gierszewska M,et al.Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein [J]. Nature, 2011,474(7353): 658-661.[JP]

[51] Bobadilla S, Sunseri N, Landau N R. Efficient transduction of myeloid cells by an HIV-1-derived lentiviral vector that packages the Vpx accessory protein[J].Gene Ther,2013,20(5):514-520.

[52] Kumar P, Ban H S, Kim S S, et al. T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice[J].Cell,2008,134(4):577-586.

[53] [JP2]Kim S S, Peer D, Kumar P, et al. RNAi-mediated CCR5 silencing by LFA-1-targeted nanoparticles prevents HIV infection in BLT mice[J]. Mol Ther, 2010, 18(2):370-376. [JP]

[54] 石英,刘宁,计云霞,等.外周血CD4++T淋巴细胞表面CCR5受体表达水平与HIV感染关系的研究[J].首都医科大学学报,2010,31(6):711-714.