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RNAi as Antiviral Therapy: The HIV-1 Case

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RNA Interference from Biology to Therapeutics

Part of the book series: Advances in Delivery Science and Technology ((ADST))

Abstract

RNA interference (RNAi) is a cellular mechanism that mediates sequence-specific gene silencing. The RNAi mechanism also has therapeutic potential, and it can be used as an antiviral approach against infectious human pathogens. An attractive target for RNAi therapeutics is the RNA genome of the human immunodeficiency virus type 1 (HIV-1). In fact, the first clinical gene therapy trial with a lentiviral vector that encodes a single RNAi inhibitor in combination with other antiviral RNA molecules was initiated in early 2008. In this chapter, we will focus on basic mechanistic principles of an RNAi-based attack on HIV-1, which in some respects forms a formidable target. Among other items, we will discuss target site selection within the viral RNA genome, the phenomenon of viral escape, and therapeutic strategies to prevent such escape. Alternatively, one could target cofactors of the host that are essential for virus replication yet less important for cell physiology. The most promising anti-escape strategy is the implementation of a combinatorial RNAi attack on the virus.

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References

  1. McCaffrey AP, Nakai H, Pandey K, Huang Z, Salazar FH, Xu H, Wieland SF, Marion PL, Kay MA (2003) Inhibition of hepatitis B virus in mice by RNA interference. Nat Biotechnol 21:639–644

    PubMed  CAS  Google Scholar 

  2. Kapadia SB, Brideau-Andersen A, Chisari FV (2003) Interference of hepatitis C virus RNA replication by short interfering RNAs. Proc Natl Acad Sci USA 100:2014–2018

    PubMed  CAS  Google Scholar 

  3. Banerjea A, Li MJ, Bauer G, Remling L, Lee NS, Rossi J, Akkina R (2003) Inhibition of HIV-1 by lentiviral vector-transduced siRNAs in T lymphocytes differentiated in SCID-hu mice and CD34+ progenitor cell-derived macrophages. Mol Ther 8:62–71

    PubMed  CAS  Google Scholar 

  4. Ter Brake O, Legrand N, von Eije KJ, Centlivre M, Spits H, Weijer K, Blom B, Berkhout B (2009) Evaluation of safety and efficacy of RNAi against HIV-1 in the human immune system (Rag-2(-/-)(c)(-/-)) mouse model. Gene Ther 16:148–153

    PubMed  Google Scholar 

  5. Ding H, Schwarz DS, Keene A, Affar EB, Fenton L, Xia X, Shi Y, Zamore PD, Xu Z (2003) Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis. Aging Cell 2:209–217

    PubMed  CAS  Google Scholar 

  6. Takeshita F, Ochiya T (2006) Therapeutic potential of RNA interference against cancer. Cancer Sci 97:689–696

    PubMed  CAS  Google Scholar 

  7. Davidson BL, Paulson HL (2004) Molecular medicine for the brain: silencing of disease genes with RNA interference. Lancet Neurol 3:145–149

    PubMed  CAS  Google Scholar 

  8. Carrington JC, Ambros V (2003) Role of microRNAs in plant and animal development. Science 301:336–338

    PubMed  CAS  Google Scholar 

  9. Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355

    PubMed  CAS  Google Scholar 

  10. Ambros V (2001) MicroRNAs: tiny regulators with great potential. Cell 107:823–826

    PubMed  CAS  Google Scholar 

  11. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    PubMed  CAS  Google Scholar 

  12. Baehrecke EH (2003) miRNAs: micro managers of programmed cell death. Curr Biol 13:R473–R475

    PubMed  CAS  Google Scholar 

  13. McManus MT (2004) Small RNAs and immunity. Immunity 21:747–756

    PubMed  CAS  Google Scholar 

  14. Lee Y, Jeon K, Lee JT, Kim S, Kim VN (2002) MicroRNA maturation: stepwise processing and subcellular localization. EMBO J 21:4663–4670

    PubMed  CAS  Google Scholar 

  15. Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004) Processing of primary microRNAs by the microprocessor complex. Nature 432:231–235

    PubMed  CAS  Google Scholar 

  16. Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R (2004) The microprocessor complex mediates the genesis of microRNAs. Nature 432:235–240

    PubMed  CAS  Google Scholar 

  17. Han J, Lee Y, Yeom KH, Kim YK, Jin H, Kim VN (2004) The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev 18:3016–3027

    PubMed  CAS  Google Scholar 

  18. Landthaler M, Yalcin A, Tuschl T (2004) The human DiGeorge syndrome critical region gene 8 and its D. melanogaster homolog are required for miRNA biogenesis. Curr Biol 14:2162–2167

    PubMed  CAS  Google Scholar 

  19. Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Radmark O, Kim S et al (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425:415–419

    PubMed  CAS  Google Scholar 

  20. Bernstein E, Caudy AA, Hammond SM, Hannon GJ (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409:363–366

    PubMed  CAS  Google Scholar 

  21. Bohnsack MT, Czaplinski K, Gorlich D (2004) Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA 10:185–191

    PubMed  CAS  Google Scholar 

  22. Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U (2004) Nuclear export of microRNA precursors. Science 303:95–98

    PubMed  CAS  Google Scholar 

  23. Yi R, Qin Y, Macara IG, Cullen BR (2003) Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 17:3011–3016

    PubMed  CAS  Google Scholar 

  24. Zhang H, Kolb FA, Jaskiewicz L, Westhof E, Filipowicz W (2004) Single processing center models for human Dicer and bacterial RNase III. Cell 118:57–68

    PubMed  CAS  Google Scholar 

  25. Chendrimada TP, Gregory RI, Kumaraswamy E, Norman J, Cooch N, Nishikura K, Shiekhattar R (2005) TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436:740–744

    PubMed  CAS  Google Scholar 

  26. Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R (2005) Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell 123:631–640

    PubMed  CAS  Google Scholar 

  27. Maniataki E, Mourelatos Z (2005) A human, ATP-independent RISC assembly machine fueled by pre-miRNA. Genes Dev 19:2979–2990

    PubMed  CAS  Google Scholar 

  28. Hammond SM, Boettcher S, Caudy AA, Kobayashi R, Hannon GJ (2001) Argonaute2, a link between genetic and biochemical analyses of RNAi. Science 293:1146–1150

    PubMed  CAS  Google Scholar 

  29. Tomari Y, Matranga C, Haley B, Martinez N, Zamore PD (2004) A protein sensor for siRNA asymmetry. Science 306:1377–1380

    PubMed  CAS  Google Scholar 

  30. Tomari Y, Zamore PD (2005) Perspective: machines for RNAi. Genes Dev 19:517–529

    PubMed  CAS  Google Scholar 

  31. Cohen MS, Hellmann N, Levy JA, DeCock K, Lange J (2008) The spread, treatment, and prevention of HIV-1: evolution of a global pandemic. J Clin Invest 118:1244–1254

    PubMed  CAS  Google Scholar 

  32. Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM (2003) Bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113:25–36

    PubMed  CAS  Google Scholar 

  33. Doench JG, Sharp PA (2004) Specificity of microRNA target selection in translational repression. Genes Dev 18:504–511

    PubMed  CAS  Google Scholar 

  34. Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB (2003) Prediction of mammalian microRNA targets. Cell 115:787–798

    PubMed  CAS  Google Scholar 

  35. Kiriakidou M, Nelson PT, Kouranov A, Fitziev P, Bouyioukos C, Mourelatos Z, Hatzigeorgiou A (2004) A combined computational-experimental approach predicts human microRNA targets. Genes Dev 18:1165–1178

    PubMed  CAS  Google Scholar 

  36. Lai EC (2002) Micro RNAs are complementary to 3’ UTR sequence motifs that mediate negative post-transcriptional regulation. Nat Genet 30:363–364

    PubMed  CAS  Google Scholar 

  37. Saetrom P, Heale BS, Snove O Jr, Aagaard L, Alluin J, Rossi JJ (2007) Distance constraints between microRNA target sites dictate efficacy and cooperativity. Nucleic Acids Res 35:2333–2342

    PubMed  CAS  Google Scholar 

  38. Yekta S, Shih IH, Bartel DP (2004) MicroRNA-directed cleavage of HOXB8 mRNA. Science 304:594–596

    PubMed  CAS  Google Scholar 

  39. Pfeffer S, Zavolan M, Grasser FA, Chien M, Russo JJ, Ju J, John B, Enright AJ, Marks D, Sander C et al (2004) Identification of virus-encoded microRNAs. Science 304:734–736

    PubMed  CAS  Google Scholar 

  40. Schopman NC, Willemsen M, Liu YP, Bradley T, van Kampen A, Baas F, Berkhout B, Haasnoot J (2012) Deep sequencing of virus-infected cells reveals HIV-encoded small RNAs. Nucleic Acids Res 40:414–427

    PubMed  CAS  Google Scholar 

  41. Parameswaran P, Sklan E, Wilkins C, Burgon T, Samuel MA, Lu R, Ansel KM, Heissmeyer V, Einav S, Jackson W et al (2010) Six RNA viruses and forty-one hosts: viral small RNAs and modulation of small RNA repertoires in vertebrate and invertebrate systems. PLoS Pathog 6:e1000764

    PubMed  Google Scholar 

  42. Yeung ML, Bennasser Y, Watashi K, Le SY, Houzet L, Jeang KT (2009) Pyrosequencing of small non-coding RNAs in HIV-1 infected cells: evidence for the processing of a viral-cellular double-stranded RNA hybrid. Nucleic Acids Res 37:6575–6586

    PubMed  CAS  Google Scholar 

  43. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498

    PubMed  CAS  Google Scholar 

  44. Brummelkamp TR, Bernards R, Agami R (2002) A system for stable expression of short interfering RNAs in mammalian cells. Science 296:550–553

    PubMed  CAS  Google Scholar 

  45. Paddison PJ, Caudy AA, Bernstein E, Hannon GJ, Conklin DS (2002) Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Dev 16:948–958

    PubMed  CAS  Google Scholar 

  46. Schopman NC, Liu YP, Konstantinova P, Ter Brake O, Berkhout B (2010) Optimization of shRNA inhibitors by variation of the terminal loop sequence. Antiviral Res 86:204–211

    PubMed  CAS  Google Scholar 

  47. Zeng Y, Wagner EJ, Cullen BR (2002) Both natural and designed micro RNAs can inhibit the expression of cognate mRNAs when expressed in human cells. Mol Cell 9:1327–1333

    PubMed  CAS  Google Scholar 

  48. Liu YP, Westerink JT, Ter Brake O, Berkhout B (2011) RNAi-inducing lentiviral vectors for anti-HIV-1 gene therapy. Methods Mol Biol 721:293–311

    PubMed  CAS  Google Scholar 

  49. Kumar P, Ban HS, Kim SS, Wu H, Pearson T, Greiner DL, Laouar A, Yao J, Haridas V, Habiro K et al (2008) T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. Cell 134:577–586

    PubMed  CAS  Google Scholar 

  50. Davis ME, Zuckerman JE, Choi CH, Seligson D, Tolcher A, Alabi CA, Yen Y, Heidel JD, Ribas A (2010) Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464:1067–1070

    PubMed  CAS  Google Scholar 

  51. Naldini L, Blomer U, Gallay P, Ory D, Mulligan R, Gage FH, Verma IM, Trono D (1996) In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272:263–267

    PubMed  CAS  Google Scholar 

  52. Nguyen TH, Oberholzer J, Birraux J, Majno P, Morel P, Trono D (2002) Highly efficient lentiviral vector-mediated transduction of nondividing, fully reimplantable primary hepatocytes. Mol Ther 6:199–209

    PubMed  CAS  Google Scholar 

  53. Liu YP, Vink MA, Westerink JT, Ramirez de Arellano E, Konstantinova P, Ter Brake O, Berkhout B (2010) Titers of lentiviral vectors encoding shRNAs and miRNAs are reduced by different mechanisms that require distinct repair strategies. RNA 16:1328–1339

    PubMed  CAS  Google Scholar 

  54. Ter Brake O, Berkhout B (2007) Lentiviral vectors that carry anti-HIV shRNAs: problems and solutions. J Gene Med 9:743–750

    PubMed  Google Scholar 

  55. Liu YP, Berkhout B (2011) miRNA cassettes in viral vectors: problems and solutions. Biochim Biophys Acta 1809:732–745

    PubMed  CAS  Google Scholar 

  56. Nguyen T, Menocal EM, Harborth J, Fruehauf JH (2008) RNAi therapeutics: an update on delivery. Curr Opin Mol Ther 10:158–167

    PubMed  CAS  Google Scholar 

  57. de Fougerolles AR (2008) Delivery vehicles for small interfering RNA in vivo. Hum Gene Ther 19:125–132

    PubMed  Google Scholar 

  58. Amado RG, Mitsuyasu RT, Rosenblatt JD, Ngok FK, Bakker A, Cole S, Chorn N, Lin LS, Bristol G, Boyd MP et al (2004) Anti-human immunodeficiency virus hematopoietic progenitor cell-delivered ribozyme in a phase I study: myeloid and lymphoid reconstitution in human immunodeficiency virus type-1-infected patients. Hum Gene Ther 15:251–262

    PubMed  CAS  Google Scholar 

  59. Mitsuyasu RT, Merigan TC, Carr A, Zack JA, Winters MA, Workman C, Bloch M, Lalezari J, Becker S, Thornton L et al (2009) Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34(+) cells. Nat Med 15:285–292

    PubMed  CAS  Google Scholar 

  60. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, Vidaud M, Abel U, Dal-Cortivo L, Caccavelli L et al (2009) Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326:818–823

    PubMed  CAS  Google Scholar 

  61. Dropulic B (2001) Lentivirus in the clinic. Mol Ther 4:511–512

    PubMed  CAS  Google Scholar 

  62. Kambal A, Mitchell G, Cary W, Gruenloh W, Jung Y, Kalomoiris S, Nacey C, McGee J, Lindsey M, Fury B et al (2011) Generation of HIV-1 resistant and functional macrophages from hematopoietic stem cell-derived induced pluripotent stem cells. Mol Ther 19:584–593

    PubMed  CAS  Google Scholar 

  63. Muesing MA, Smith DH, Cabradilla CD, Benton CV, Lasky LA, Capon DJ (1985) Nucleic acid structure and expression of the human AIDS/lymphadenopathy retrovirus. Nature 313:450–458

    PubMed  CAS  Google Scholar 

  64. Westerhout EM, Ooms M, Vink M, Das AT, Berkhout B (2005) HIV-1 can escape from RNA interference by evolving an alternative structure in its RNA genome. Nucleic Acids Res 33:796–804

    PubMed  CAS  Google Scholar 

  65. Westerhout EM, Berkhout B (2007) A systematic analysis of the effect of target RNA structure on RNA interference. Nucleic Acids Res 35:4322–4330

    PubMed  CAS  Google Scholar 

  66. Watts JM, Dang KK, Gorelick RJ, Leonard CW, Bess JW Jr, Swanstrom R, Burch CL, Weeks KM (2009) Architecture and secondary structure of an entire HIV-1 RNA genome. Nature 460:711–716

    PubMed  CAS  Google Scholar 

  67. Low JT, Knoepfel SA, Watts JM, ter Brake O, Berkhout B, Weeks KM (2012) SHAPE-directed discovery of potent shRNA inhibitors of HIV-1 Mol Ther: 20(4):820–828

    PubMed  CAS  Google Scholar 

  68. Kafri T, Blomer U, Peterson DA, Gage FH, Verma IM (1997) Sustained expression of genes delivered directly into liver and muscle by lentiviral vectors. Nat Genet 17:314–317

    PubMed  CAS  Google Scholar 

  69. Ter Brake O, Konstantinova P, Ceylan M, Berkhout B (2006) Silencing of HIV-1 with RNA interference: a multiple shRNA approach. Mol Ther 14:883–892

    PubMed  Google Scholar 

  70. von Eije KJ, Ter Brake O, Berkhout B (2009) Stringent testing identifies highly potent and escape-proof anti-HIV short hairpin RNAs. J Gene Med 11:459–467

    Google Scholar 

  71. McIntyre GJ, Groneman JL, Yu YH, Jaramillo A, Shen S, Applegate TL (2009) 96 shRNAs designed for maximal coverage of HIV-1 variants. Retrovirology 6:55

    PubMed  Google Scholar 

  72. Jacque JM, Triques K, Stevenson M (2002) Modulation of HIV-1 replication by RNA interference. Nature 418:435–438

    PubMed  CAS  Google Scholar 

  73. Chang LJ, Liu X, He J (2005) Lentiviral siRNAs targeting multiple highly conserved RNA sequences of human immunodeficiency virus type 1. Gene Ther 12:1133–1144

    PubMed  CAS  Google Scholar 

  74. Novina CD, Murray MF, Dykxhoorn DM, Beresford PJ, Riess J, Lee SK, Collman RG, Lieberman J, Shankar P, Sharp PA (2002) siRNA-directed inhibition of HIV-1 infection. Nat Med 8:681–686

    PubMed  CAS  Google Scholar 

  75. Park WS, Miyano-Kurosaki N, Hayafune M, Nakajima E, Matsuzaki T, Shimada F, Takaku H (2002) Prevention of HIV-1 infection in human peripheral blood mononuclear cells by specific RNA interference. Nucleic Acids Res 30:4830–4835

    PubMed  CAS  Google Scholar 

  76. Berkhout B, Ter Brake O (2008) Towards an RNAi-based gene therapy. BIOforum Europe 4:35–37

    Google Scholar 

  77. Surabhi RM, Gaynor RB (2002) RNA interference directed against viral and cellular targets inhibits human immunodeficiency virus type 1 replication. J Virol 76:12963–12973

    PubMed  CAS  Google Scholar 

  78. Coburn GA, Cullen BR (2002) Potent and specific inhibition of human immunodeficiency virus type 1 replication by RNA interference. J Virol 76:9225–9231

    PubMed  CAS  Google Scholar 

  79. Lee NS, Dohjima T, Bauer G, Li H, Li MJ, Ehsani A, Salvaterra P, Rossi J (2002) Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells. Nat Biotechnol 20:500–505

    PubMed  CAS  Google Scholar 

  80. Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M, Li B, Cavet G, Linsley PS (2003) Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol 21:635–637

    PubMed  CAS  Google Scholar 

  81. Robbins M, Judge A, Ambegia E, Choi C, Yaworski E, Palmer L, McClintock K, Maclachlan I (2008) Misinterpreting the therapeutic effects of siRNA caused by immune stimulation. Hum Gene Ther 19:991–999

    PubMed  CAS  Google Scholar 

  82. Kleinman ME, Yamada K, Takeda A, Chandrasekaran V, Nozaki M, Baffi JZ, Albuquerque RJ, Yamasaki S, Itaya M, Pan Y et al (2008) Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452:591–597

    PubMed  CAS  Google Scholar 

  83. Ter Brake O, ‘t Hooft K, Liu YP, Centlivre M, von Eije KJ, Berkhout B (2008) Lentiviral vector design for multiple shRNA expression and durable HIV-1 inhibition. Mol Ther 16:557–564

    PubMed  Google Scholar 

  84. von Eije KJ, Ter Brake O, Berkhout B (2008) Human immunodeficiency virus type 1 escape is restricted when conserved genome sequences are targeted by RNA interference. J Virol 82:2895–2903

    Google Scholar 

  85. Boden D, Pusch O, Lee F, Tucker L, Ramratnam B (2003) Human immunodeficiency virus type 1 escape from RNA interference. J Virol 77:11531–11535

    PubMed  CAS  Google Scholar 

  86. Das AT, Brummelkamp TR, Westerhout EM, Vink M, Madiredjo M, Bernards R, Berkhout B (2004) Human immunodeficiency virus type 1 escapes from RNA interference-mediated inhibition. J Virol 78:2601–2605

    PubMed  CAS  Google Scholar 

  87. Nishitsuji H, Kohara M, Kannagi M, Masuda T (2006) Effective suppression of human immunodeficiency virus type 1 through a combination of short- or long-hairpin RNAs targeting essential sequences for retroviral integration. J Virol 80:7658–7666

    PubMed  CAS  Google Scholar 

  88. Sabariegos R, Gimenez-Barcons M, Tapia N, Clotet B, Martinez MA (2006) Sequence homology required by human immunodeficiency virus type 1 to escape from short interfering RNAs. J Virol 80:571–577

    PubMed  CAS  Google Scholar 

  89. Unwalla HJ, Li HT, Bahner I, Li MJ, Kohn D, Rossi JJ (2006) Novel Pol II fusion promoter directs human immunodeficiency virus type 1-inducible coexpression of a short hairpin RNA and protein. J Virol 80:1863–1873

    PubMed  CAS  Google Scholar 

  90. Leonard JN, Shah PS, Burnett JC, Schaffer DV (2008) HIV evades RNA interference directed at TAR by an indirect compensatory mechanism. Cell Host Microbe 4:484–494

    PubMed  CAS  Google Scholar 

  91. Berkhout B (2009) A new Houdini act: multiple routes for HIV-1 escape from RNAi-mediated inhibition. Future Microbiol 4:151–154

    PubMed  CAS  Google Scholar 

  92. Hache G, Abbink TE, Berkhout B, Harris RS (2009) Optimal translation initiation enables Vif-deficient human immunodeficiency virus type 1 to escape restriction by APOBEC3G. J Virol 83:5956–5960

    PubMed  CAS  Google Scholar 

  93. Hache G, Shindo K, Albin JS, Harris RS (2008) Evolution of HIV-1 isolates that use a novel Vif-independent mechanism to resist restriction by human APOBEC3G. Curr Biol 18:819–824

    PubMed  CAS  Google Scholar 

  94. Das AT, Berkhout B (2010) HIV-1 evolution: frustrating therapies, but disclosing molecular mechanisms. Philos Trans R Soc Lond B Biol Sci 365:1965–1973

    PubMed  CAS  Google Scholar 

  95. Li MJ, Kim J, Li S, Zaia J, Yee JK, Anderson J, Akkina R, Rossi JJ (2005) Long-term inhibition of HIV-1 infection in primary hematopoietic cells by lentiviral vector delivery of a triple combination of anti-HIV shRNA, anti-CCR5 ribozyme, and a nucleolar-localizing TAR decoy. Mol Ther 12:900–909

    PubMed  CAS  Google Scholar 

  96. DiGiusto DL, Krishnan A, Li L, Li H, Li S, Rao A, Mi S, Yam P, Stinson S, Kalos M et al (2010) RNA-based gene therapy for HIV with lentiviral vector-modified CD34(+) cells in patients undergoing transplantation for AIDS-related lymphoma. Sci Transl Med 2:36ra43

    PubMed  Google Scholar 

  97. Neff CP, Zhou J, Remling L, Kuruvilla J, Zhang J, Li H, Smith DD, Swiderski P, Rossi JJ, Akkina R (2011) An aptamer-siRNA chimera suppresses HIV-1 viral loads and protects from helper CD4(+) T cell decline in humanized mice. Sci Transl Med 3:66ra6

    PubMed  Google Scholar 

  98. Wang GP, Levine BL, Binder GK, Berry CC, Malani N, McGarrity G, Tebas P, June CH, Bushman FD (2009) Analysis of lentiviral vector integration in HIV  +  study subjects receiving autologous infusions of gene modified CD4+ T cells. Mol Ther 17:844–850

    PubMed  CAS  Google Scholar 

  99. Ter Brake O, Berkhout B (2005) A novel approach for inhibition of HIV-1 by RNA interference: counteracting viral escape with a second generation of siRNAs. J RNAi Gene Silencing 1:56–65

    PubMed  Google Scholar 

  100. Schopman NC, Ter Brake O, Berkhout B (2010) Anticipating and blocking HIV-1 escape by second generation antiviral shRNAs. Retrovirology 7:52

    PubMed  Google Scholar 

  101. Schopman NC, Braun A, Berkhout B (2012) Directed HIV-1 evolution of protease inhibitor resistance by second-generation short hairpin RNAs. Antimicrob Agents Chemother 56:479–486

    PubMed  CAS  Google Scholar 

  102. Berkhout B, Sanders RW (2011) Molecular strategies to design an escape-proof antiviral therapy. Antiviral Res 92:7–14

    PubMed  CAS  Google Scholar 

  103. Ter Brake O, Berkhout B (2008) Development of an RNAi-based gene therapy against HIV-1. In: Kurreck J (ed) Therapeutic oligonucleotides. RSC Publishing, Cambridge, pp 296–311

    Google Scholar 

  104. Liu YP, Haasnoot J, Berkhout B (2007) Design of extended short hairpin RNAs for HIV-1 inhibition. Nucleic Acids Res 35:5683–5693

    PubMed  CAS  Google Scholar 

  105. Liu YP, von Eije KJ, Schopman NC, Westerink JT, Ter Brake O, Haasnoot J, Berkhout B (2009) Combinatorial RNAi against HIV-1 using extended short hairpin RNAs. Mol Ther 17:1712–1723

    PubMed  CAS  Google Scholar 

  106. Saayman S, Barichievy S, Capovilla A, Morris KV, Arbuthnot P, Weinberg MS (2008) The efficacy of generating three independent anti-HIV-1 siRNAs from a single U6 RNA Pol III-expressed long hairpin RNA. PLoS One 3:e2602

    PubMed  Google Scholar 

  107. Barichievy S, Saayman S, von Eije KJ, Morris KV, Arbuthnot P, Weinberg MS (2007) The inhibitory efficacy of RNA POL III-expressed long hairpin RNAs targeted to untranslated regions of the HIV-1 5’ long terminal repeat. Oligonucleotides 17:419–431

    PubMed  CAS  Google Scholar 

  108. Sano M, Li H, Nakanishi M, Rossi JJ (2008) Expression of long anti-HIV-1 hairpin RNAs for the generation of multiple siRNAs: advantages and limitations. Mol Ther 16:170–177

    PubMed  CAS  Google Scholar 

  109. Konstantinova P, de Vries W, Haasnoot J, Ter Brake O, de Haan P, Berkhout B (2006) Inhibition of human immunodeficiency virus type 1 by RNA interference using long-hairpin RNA. Gene Ther 13:1403–1413

    PubMed  CAS  Google Scholar 

  110. Liu YP, Haasnoot J, Ter Brake O, Berkhout B, Konstantinova P (2008) Inhibition of HIV-1 by multiple siRNAs expressed from a single microRNA polycistron. Nucleic Acids Res 36:2811–2824

    PubMed  CAS  Google Scholar 

  111. Grimm D, Streetz KL, Jopling CL, Storm TA, Pandey K, Davis CR, Marion P, Salazar F, Kay MA (2006) Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441:537–541

    PubMed  CAS  Google Scholar 

  112. McBride JL, Boudreau RL, Harper SQ, Staber PD, Monteys AM, Martins I, Gilmore BL, Burstein H, Peluso RW, Polisky B et al (2008) Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. Proc Natl Acad Sci USA 105:5868–5873

    PubMed  CAS  Google Scholar 

  113. Castanotto D, Sakurai K, Lingeman R, Li H, Shively L, Aagaard L, Soifer H, Gatignol A, Riggs A, Rossi JJ (2007) Combinatorial delivery of small interfering RNAs reduces RNAi efficacy by selective incorporation into RISC. Nucleic Acids Res 35:5154–5164

    PubMed  CAS  Google Scholar 

  114. Vickers TA, Lima WF, Nichols JG, Crooke ST (2007) Reduced levels of Ago2 expression result in increased siRNA competition in mammalian cells. Nucleic Acids Res 35:6598–6610

    PubMed  CAS  Google Scholar 

  115. Snyder LL, Esser JM, Pachuk CJ, Steel LF (2008) Vector design for liver-specific expression of multiple interfering RNAs that target hepatitis B virus transcripts. Antiviral Res 80:36–44

    PubMed  CAS  Google Scholar 

  116. Wiznerowicz M, Trono D (2003) Conditional suppression of cellular genes: lentivirus vector-mediated drug-inducible RNA interference. J Virol 77:8957–8961

    PubMed  CAS  Google Scholar 

  117. Zhou X, Symons J, Hoppes R, Krueger C, Berens C, Hillen W, Berkhout B, Das AT (2007) Improved single-chain transactivators of the Tet-On gene expression system. BMC Biotechnol 7:6

    PubMed  Google Scholar 

  118. Grimm D, Kay MA (2007) Combinatorial RNAi: a winning strategy for the race against evolving targets? Mol Ther 15:878–888

    PubMed  CAS  Google Scholar 

  119. Liu YP, Berkhout B (2008) Combinatorial RNAi strategies against HIV-1 and other escape-prone viruses. Int J Biosci Technol 1:1–10

    Google Scholar 

  120. Lisziewicz J, Sun D, Smythe J, Lusso P, Lori F, Louie A, Markham P, Rossi J, Reitz M, Gallo RC (1993) Inhibition of human immunodeficiency virus type 1 replication by regulated expression of a polymeric Tat activation response RNA decoy as a strategy for gene therapy in AIDS. Proc Natl Acad Sci USA 90:8000–8004

    PubMed  CAS  Google Scholar 

  121. Sarver N, Cantin EM, Chang PS, Zaia JA, Ladne PA, Stephens DA, Rossi JJ (1990) Ribozymes as potential anti-HIV-1 therapeutic agents. Science 247:1222–1225

    PubMed  CAS  Google Scholar 

  122. Chatterjee S, Johnson PR, Wong KK Jr (1992) Dual-target inhibition of HIV-1 in vitro by means of an adeno-associated virus antisense vector. Science 258:1485–1488

    PubMed  CAS  Google Scholar 

  123. Levine BL, Humeau LM, Boyer J, MacGregor RR, Rebello T, Lu X, Binder GK, Slepushkin V, Lemiale F, Mascola JR et al (2006) Gene transfer in humans using a conditionally replicating lentiviral vector. Proc Natl Acad Sci USA 103:17372–17377

    PubMed  CAS  Google Scholar 

  124. Kohn DB, Bauer G, Rice CR, Rothschild JC, Carbonaro DA, Valdez P, Hao Q, Zhou C, Bahner I, Kearns K et al (1999) A clinical trial of retroviral-mediated transfer of a rev-responsive element decoy gene into CD34(+) cells from the bone marrow of human immunodeficiency virus-1-infected children. Blood 94:368–371

    PubMed  CAS  Google Scholar 

  125. Symensma TL, Giver L, Zapp M, Takle GB, Ellington AD (1996) RNA aptamers selected to bind human immunodeficiency virus type 1 Rev in vitro are Rev responsive in vivo. J Virol 70:179–187

    PubMed  CAS  Google Scholar 

  126. Weinberg MS, Villeneuve LM, Ehsani A, Amarzguioui M, Aagaard L, Chen ZX, Riggs AD, Rossi JJ, Morris KV (2006) The antisense strand of small interfering RNAs directs histone methylation and transcriptional gene silencing in human cells. RNA 12:256–262

    PubMed  CAS  Google Scholar 

  127. Abad X, Vera M, Jung SP, Oswald E, Romero I, Amin V, Fortes P, Gunderson SI (2008) Requirements for gene silencing mediated by U1 snRNA binding to a target sequence. Nucleic Acids Res 36:2338–2352

    PubMed  CAS  Google Scholar 

  128. Knoepfel SA, Abad A, Abad X, Fortes P, Berkhout B (2012) Design of modified U1i molecules against HIV-1 RNA. Antiviral Res.94(3):208–216.

    PubMed  CAS  Google Scholar 

  129. Anderson J, Banerjea A, Akkina R (2003) Bispecific short hairpin siRNA constructs targeted to CD4, CXCR4, and CCR5 confer HIV-1 resistance. Oligonucleotides 13:303–312

    PubMed  CAS  Google Scholar 

  130. Martinez J, Patkaniowska A, Urlaub H, Luhrmann R, Tuschl T (2002) Single-stranded antisense siRNAs guide target RNA cleavage in RNAi. Cell 110:563–574

    PubMed  CAS  Google Scholar 

  131. Anderson J, Akkina R (2005) CXCR4 and CCR5 shRNA transgenic CD34+ cell derived macrophages are functionally normal and resist HIV-1 infection. Retrovirology 2:53

    PubMed  Google Scholar 

  132. Anderson J, Banerjea A, Planelles V, Akkina R (2003) Potent suppression of HIV type 1 infection by a short hairpin anti-CXCR4 siRNA. AIDS Res Hum Retroviruses 19:699–706

    PubMed  CAS  Google Scholar 

  133. Ishaq M, Hu J, Wu X, Fu Q, Yang Y, Liu Q, Guo D (2008) Knockdown of cellular RNA helicase DDX3 by short hairpin RNAs suppresses HIV-1 viral replication without inducing apoptosis. Mol Biotechnol 39:231–238

    PubMed  CAS  Google Scholar 

  134. Vandekerckhove L, Christ F, Van Maele B, De Rijck J, Gijsbers R, Van den HC, Witvrouw M, Debyser Z (2006) Transient and stable knockdown of the integrase cofactor LEDGF/p75 reveals its role in the replication cycle of human immunodeficiency virus. J Virol 80:1886–1896

    PubMed  CAS  Google Scholar 

  135. An DS, Donahue RE, Kamata M, Poon B, Metzger M, Mao SH, Bonifacino A, Krouse AE, Darlix JL, Baltimore D et al (2007) Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates. Proc Natl Acad Sci USA 104: 13110–13115

    PubMed  CAS  Google Scholar 

  136. Eekels JJM, Geerts D, Jeeninga RE, Berkhout B (2011) Long-term inhibition of HIV-1 replication with RNA interference against cellular cofactors. Antiviral Res 89:43–53

    PubMed  CAS  Google Scholar 

  137. Lim JK, Glass WG, McDermott DH, Murphy PM (2006) CCR5: no longer a “good for nothing” gene–chemokine control of West Nile virus infection. Trends Immunol 27:308–312

    PubMed  CAS  Google Scholar 

  138. Liu Z, Yang F, Robotham JM, Tang H (2009) Critical role of cyclophilin A and its prolyl-peptidyl isomerase activity in the structure and function of the hepatitis C virus replication complex. J Virol 83:6554–6565

    PubMed  CAS  Google Scholar 

  139. Allers K, Hutter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E, Schneider T (2010) Evidence for the cure of HIV infection by CCR5{Delta}32/{Delta}32 stem cell transplantation. Blood 117(10):2791–2799

    PubMed  Google Scholar 

  140. Bangsberg DR, Charlebois ED, Grant RM, Holodniy M, Deeks SG, Perry S, Conroy KN, Clark R, Guzman D, Zolopa A et al (2003) High levels of adherence do not prevent accumulation of HIV drug resistance mutations. AIDS 17:1925–1932

    PubMed  Google Scholar 

  141. Menendez-Arias L (2010) Molecular basis of human immunodeficiency virus drug resistance: an update. Antiviral Res 85:210–231

    PubMed  CAS  Google Scholar 

  142. Lapidot T (2001) Mechanism of human stem cell migration and repopulation of NOD/SCID and B2mnull NOD/SCID mice. The role of SDF-1/CXCR4 interactions. Ann N Y Acad Sci 938:83–95

    PubMed  CAS  Google Scholar 

  143. Yang F, Robotham JM, Nelson HB, Irsigler A, Kenworthy R, Tang H (2008) Cyclophilin A is an essential cofactor for hepatitis C virus infection and the principal mediator of cyclosporine resistance in vitro. J Virol 82:5269–5278

    PubMed  CAS  Google Scholar 

  144. Gaspar HB, Thrasher AJ (2005) Gene therapy for severe combined immunodeficiencies. Expert Opin Biol Ther 5:1175–1182

    PubMed  CAS  Google Scholar 

  145. Parkin NT, Chamorro M, Varmus HE (1992) Human immunodeficiency virus type 1 gag-pol frameshifting is dependent on downstream mRNA secondary structure: demonstration by expression in vivo. J Virol 66:5147–5151

    PubMed  CAS  Google Scholar 

  146. Goff SP (2008) Knockdown screens to knockout HIV-1. Cell 135:417–420

    PubMed  CAS  Google Scholar 

  147. Eekels JJM, Berkhout B (2011) Toward a durable treatment of HIV-1 infection using RNA interference. In: Grimm D (ed) Cellular RNA interference mechanisms, vol 102. Elsevier, London, pp 141–163

    Google Scholar 

  148. Bushman FD, Malani N, Fernandes J, D’Orso I, Cagney G, Diamond TL, Zhou H, Hazuda DJ, Espeseth AS, Konig R et al (2009) Host cell factors in HIV replication: meta-analysis of genome-wide studies. PLoS Pathog 5:e1000437

    PubMed  Google Scholar 

  149. Karlas A, Machuy N, Shin Y, Pleissner KP, Artarini A, Heuer D, Becker D, Khalil H, Ogilvie LA, Hess S et al (2010) Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication. Nature 463:818–822

    PubMed  CAS  Google Scholar 

  150. Konig R, Stertz S, Zhou Y, Inoue A, Hoffmann HH, Bhattacharyya S, Alamares JG, Tscherne DM, Ortigoza MB, Liang Y et al (2010) Human host factors required for influenza virus replication. Nature 463:813–817

    PubMed  Google Scholar 

  151. Li Q, Brass AL, Ng A, Hu Z, Xavier RJ, Liang TJ, Elledge SJ (2009) A genome-wide genetic screen for host factors required for hepatitis C virus propagation. Proc Natl Acad Sci USA 106:16410–16415

    PubMed  CAS  Google Scholar 

  152. Sessions OM, Barrows NJ, Souza-Neto JA, Robinson TJ, Hershey CL, Rodgers MA, Ramirez JL, Dimopoulos G, Yang PL, Pearson JL et al (2009) Discovery of insect and human dengue virus host factors. Nature 458:1047–1050

    PubMed  CAS  Google Scholar 

  153. van den Berg CH, Smit C, Bakker M, Geskus RB, Berkhout B, Jurriaans S, Coutinho RA, Wolthers KC, Prins M (2007) Major decline of hepatitis C virus incidence rate over two decades in a cohort of drug users. Eur J Epidemiol 22:183–193

    PubMed  Google Scholar 

  154. Wheatley AK, Kramski M, Alexander MR, Toe JG, Center RJ, Purcell DF (2011) Co-expression of miRNA targeting the expression of PERK, but not PKR, enhances cellular immunity from an HIV-1 Env DNA vaccine. PLoS One 6:e18225

    PubMed  CAS  Google Scholar 

  155. Liu Z, Robida JM, Chinnaswamy S, Yi G, Robotham JM, Nelson HB, Irsigler A, Kao CC, Tang H (2009) Mutations in the hepatitis C virus polymerase that increase RNA binding can confer resistance to cyclosporine A. Hepatology 50(1):25–33

    PubMed  CAS  Google Scholar 

  156. Boudreau RL, Monteys AM, Davidson BL (2008) Minimizing variables among hairpin-based RNAi vectors reveals the potency of shRNAs. RNA 14:1834–1844

    PubMed  CAS  Google Scholar 

  157. Brennecke J, Stark A, Russell RB, Cohen SM (2005) Principles of microRNA-target recognition. PLoS Biol 3:e85

    PubMed  Google Scholar 

  158. Fedorov Y, Anderson EM, Birmingham A, Reynolds A, Karpilow J, Robinson K, Leake D, Marshall WS, Khvorova A (2006) Off-target effects by siRNA can induce toxic phenotype. RNA 12:1188–1196

    PubMed  CAS  Google Scholar 

  159. Jackson AL, Burchard J, Schelter J, Chau BN, Cleary M, Lim L, Linsley PS (2006) Widespread siRNA “off-target” transcript silencing mediated by seed region sequence complementarity. RNA 12:1179–1187

    PubMed  CAS  Google Scholar 

  160. Bridge AJ, Pebernard S, Ducraux A, Nicoulaz AL, Iggo R (2003) Induction of an interferon response by RNAi vectors in mammalian cells. Nat Genet 34:263–264

    PubMed  CAS  Google Scholar 

  161. Sledz CA, Holko M, de Veer MJ, Silverman RH, Williams BR (2003) Activation of the interferon system by short-interfering RNAs. Nat Cell Biol 5:834–839

    PubMed  CAS  Google Scholar 

  162. Marques JT, Williams BR (2005) Activation of the mammalian immune system by siRNAs. Nat Biotechnol 23:1399–1405

    PubMed  CAS  Google Scholar 

  163. Eekels JJM, Pasternak AO, Schut AM, Geerts D, Jeeninga RE, Berkhout B (2012) A competitive cell growth assay for the detection of subtle effects of gene transduction on cell proliferation. Gene Ther. Advance online publication. doi: 10.1038/gt.2011.191.

    Google Scholar 

  164. Lackner AA, Veazey RS (2007) Current concepts in AIDS pathogenesis: insights from the SIV/macaque model. Annu Rev Med 58:461–476

    PubMed  CAS  Google Scholar 

  165. Stremlau M, Owens CM, Perron MJ, Kiessling M, Autissier P, Sodroski J (2004) The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys. Nature 427:848–853

    PubMed  CAS  Google Scholar 

  166. Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti JC, Lanzavecchia A, Manz MG (2004) Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 304:104–107

    PubMed  CAS  Google Scholar 

  167. Gimeno R, Weijer K, Voordouw A, Uittenbogaart CH, Legrand N, Alves NL, Wijnands E, Blom B, Spits H (2004) Monitoring the effect of gene silencing by RNA interference in human CD34+ cells injected into newborn RAG2-/- gammac-/- mice: functional inactivation of p53 in developing T cells. Blood 104:3886–3893

    PubMed  CAS  Google Scholar 

  168. Legrand N, Weijer K, Spits H (2006) Experimental models to study development and function of the human immune system in vivo. J Immunol 176:2053–2058

    PubMed  CAS  Google Scholar 

  169. Shultz LD, Ishikawa F, Greiner DL (2007) Humanized mice in translational biomedical research. Nat Rev Immunol 7:118–130

    PubMed  CAS  Google Scholar 

  170. Manz MG (2007) Human-hemato-lymphoid-system mice: opportunities and challenges. Immunity 26:537–541

    PubMed  CAS  Google Scholar 

  171. Legrand N, Cupedo T, van Lent AU, Ebeli MJ, Weijer K, Hanke T, Spits H (2006) Transient accumulation of human mature thymocytes and regulatory T cells with CD28 superagonist in “human immune system” Rag2(-/-)gammac(-/-) mice. Blood 108:238–245

    PubMed  CAS  Google Scholar 

  172. Baenziger S, Tussiwand R, Schlaepfer E, Mazzucchelli L, Heikenwalder M, Kurrer MO, Behnke S, Frey J, Oxenius A, Joller H et al (2006) Disseminated and sustained HIV infection in CD34+ cord blood cell-transplanted Rag2-/-gamma c-/- mice. Proc Natl Acad Sci USA 103:15951–15956

    PubMed  CAS  Google Scholar 

  173. Zhang L, Kovalev GI, Su L (2007) HIV-1 infection and pathogenesis in a novel humanized mouse model. Blood 109:2978–2981

    PubMed  CAS  Google Scholar 

  174. Watanabe S, Terashima K, Ohta S, Horibata S, Yajima M, Shiozawa Y, Dewan MZ, Yu Z, Ito M, Morio T et al (2007) Hematopoietic stem cell-engrafted NOD/SCID/IL2Rgamma null mice develop human lymphoid systems and induce long-lasting HIV-1 infection with specific humoral immune responses. Blood 109:212–218

    PubMed  CAS  Google Scholar 

  175. Berges BK, Wheat WH, Palmer BE, Connick E, Akkina R (2006) HIV-1 infection and CD4 T cell depletion in the humanized Rag2-/-gamma c-/- (RAG-hu) mouse model. Retrovirology 3:76

    PubMed  Google Scholar 

  176. Berges BK, Akkina SR, Folkvord JM, Connick E, Akkina R (2008) Mucosal transmission of R5 and X4 tropic HIV-1 via vaginal and rectal routes in humanized Rag2(-/-)gammac(-/-) (RAG-hu) mice. Virology 373:342–351

    PubMed  CAS  Google Scholar 

  177. An DS, Poon B, Ho Tsong FR, Weijer K, Blom B, Spits H, Chen IS, Uittenbogaart CH (2007) Use of a novel chimeric mouse model with a functionally active human immune system to study human immunodeficiency virus type 1 infection. Clin Vaccine Immunol 14:391–396

    PubMed  CAS  Google Scholar 

  178. Goldstein H (2008) Summary of presentations at the NIH/NIAID New Humanized Rodent Models 2007 Workshop. AIDS Res Ther 5:3

    PubMed  Google Scholar 

  179. Edelstein ML, Abedi MR, Wixon J (2007) Gene therapy clinical trials worldwide to 2007–an update. J Gene Med 9:833–842

    PubMed  Google Scholar 

  180. Culliton BJ (1990) Gene therapy begins. Science 249:1372

    PubMed  CAS  Google Scholar 

  181. Marshall E (1999) Gene therapy death prompts review of adenovirus vector. Science 286:2244–2245

    PubMed  CAS  Google Scholar 

  182. Hacein-Bey-Abina S, Le Deist F, Carlier F, Bouneaud C, Hue C, de Villartay JP, Thrasher AJ, Wulffraat N, Sorensen R, Dupuis-Girod S et al (2002) Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med 346:1185–1193

    PubMed  CAS  Google Scholar 

  183. Hacein-Bey-Abina S, von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E et al (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302:415–419

    PubMed  CAS  Google Scholar 

  184. Cavazzana-Calvo M, Fischer A (2007) Gene therapy for severe combined immunodeficiency: are we there yet? J Clin Invest 117:1456–1465

    PubMed  CAS  Google Scholar 

  185. Robotham JM, Nelson HB, Tang H (2009) Selection and characterization of drug-resistant HCV replicons in vitro with a flow cytometry-based assay. Methods Mol Biol 510:227–242

    PubMed  CAS  Google Scholar 

  186. Bushman F, Lewinski M, Ciuffi A, Barr S, Leipzig J, Hannenhalli S, Hoffmann C (2005) Genome-wide analysis of retroviral DNA integration. Nat Rev Microbiol 3:848–858

    PubMed  CAS  Google Scholar 

  187. Montini E, Cesana D, Schmidt M, Sanvito F, Ponzoni M, Bartholomae C, Sergi SL, Benedicenti F, Ambrosi A, Di Serio C et al (2006) Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. Nat Biotechnol 24:687–696

    PubMed  CAS  Google Scholar 

  188. Manilla P, Rebello T, Afable C, Lu X, Slepushkin V, Humeau LM, Schonely K, Ni Y, Binder GK, Levine BL et al (2005) Regulatory considerations for novel gene therapy products: a review of the process leading to the first clinical lentiviral vector. Hum Gene Ther 16:17–25

    PubMed  CAS  Google Scholar 

  189. Rossi JJ, June CH, Kohn DB (2007) Genetic therapies against HIV. Nat Biotechnol 25:1444–1454

    PubMed  CAS  Google Scholar 

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Acknowledgments

RNAi research in the Berkhout lab is sponsored by ZonMw (Translational gene therapy program) and the Dutch AIDS Fund (grant number 2006006). We also thank the Belgian Federal Government for financial support through the Inter-University Attraction Pole grant no. P6/41.

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  1. Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Ben Berkhout & Julia J. M. Eekels

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  1. Ben Berkhout
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Correspondence to Ben Berkhout .

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  1. Interdisciplinary Nanoscience Center, Aarhus University, Ny Munkegade 118, Aarhus, 8000 AA, Denmark

    Kenneth A. Howard

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Berkhout, B., Eekels, J.J.M. (2013). RNAi as Antiviral Therapy: The HIV-1 Case. In: Howard, K. (eds) RNA Interference from Biology to Therapeutics. Advances in Delivery Science and Technology. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-4744-3_11

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