CoChat
Sign Up
Cited by 60Virus-based gene therapy researchRNA Interference and Gene DeliveryCRISPR and Genetic Engineering

Design and potential of non-integrating lentiviral vectors

Open access
Shaw, Aaron, Cornetta, Kenneth·2014·Biomedicines
DOI 10.3390/biomedicines2010014PMC PMC5423482
Open this paper in CoChat — free accountOpen PDF

Abstract

Lentiviral vectors have demonstrated promising results in clinical trials that target cells of the hematopoietic system. For these applications, they are the vectors of choice since they provide stable integration into cells that will undergo extensive expansion in vivo. Unfortunately, integration can have unintended consequences including dysregulated cell growth. Therefore, lentiviral vectors that do not integrate are predicted to have a safer profile compared to integrating vectors and should be considered for applications where transient expression is required or for sustained episomal expression such as in quiescent cells. In this review, the system for generating lentiviral vectors will be described and used to illustrate how alterations in the viral integrase or vector Long Terminal Repeats have been used to generate vectors that lack the ability to integrate. In addition to their safety advantages, these non-integrating lentiviral vectors can be used when persistent expression would have adverse consequences. Vectors are currently in development for use in vaccinations, cancer therapy, site-directed gene insertions, gene disruption strategies, and cell reprogramming. Preclinical work will be described that illustrates the potential of this unique vector system in human gene therapy.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3390/biomedicines2010014

Cites

23 of 23 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 128

  1. [1]Cronin J. Zhang X.Y. Reiser J. Altering the tropism of lentiviral vectors through pseudotyping Curr. Gene Ther. 2005 5 387 398 10.2174/1566523054546224 16101513 PMC1368960 · DOI
  2. [2]Clapham P.R. McKnight A. Cell surface receptors, virus entry and tropism of primate lentiviruses J. Gen. Virol. 2002 83 1809 1829 12124446
  3. [3]Kumar M. Keller B. Makalou N. Sutton R.E. Systematic determination of the packaging limit of lentiviral vectors Hum. Gene Ther. 2001 12 1893 1905 10.1089/104303401753153947 11589831 · DOI
  4. [4]Sinn P.L. Sauter S.L. McCray P.B. Jr. Gene therapy progress and prospects: Development of improved lentiviral and retroviral vectors—Design, biosafety, and production Gene Ther. 2005 12 1089 1098 10.1038/sj.gt.3302570 16003340 · DOI
  5. [6]Blomer U. Naldini L. Kafri T. Trono D. Verma I.M. Gage F.H. Highly efficient and sustained gene transfer in adult neurons with a lentivirus vector J. Virol. 1997 71 6641 6649 9261386 PMC191942
  6. [7]Abordo-Adesida E. Follenzi A. Barcia C. Sciascia S. Castro M.G. Naldini L. Lowenstein P.R. Stability of lentiviral vector-mediated transgene expression in the brain in the presence of systemic antivector immune responses Hum. Gene Ther. 2005 16 741 751 10.1089/hum.2005.16.741 15960605 PMC2676203 · DOI
  7. [8]Bischof D. Cornetta K. Detection of replication competent retrovirus and lentivirus Methods in Molecular Biology: Genetic Modification of Hematopoietic Stem Cells: Methods and Protocols Baum C. Humana Press, Inc. Totowa, NJ, USA 2008 243 263 19110631
  8. [9]Cavazzana-Calvo M. Payen E. Negre O. Wang G. Hehir K. Fusil F. Down J. Denaro M. Brady T. Westerman K. Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia Nature 2010 467 318 322 10.1038/nature09328 20844535 PMC3355472 · DOI · Paper page
  9. [10]Aiuti A. Biasco L. Scaramuzza S. Ferrua F. Cicalese M.P. Baricordi C. Dionisio F. Calabria A. Giannelli S. Castiello M.C. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome Science 2013 341 10.1126/science.1233151 PMC4375961 23845947 · DOI · Paper page
  10. [11]Biffi A. Montini E. Lorioli L. Cesani M. Fumagalli F. Plati T. Baldoli C. Martino S. Calabria A. Canale S. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy Science 2013 341 10.1126/science.1233158 23845948 · DOI · Paper page
  11. [13]Porter D.L. Levine B.L. Kalos M. Bagg A. June C.H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia N. Engl. J. Med. 2011 365 725 733 10.1056/NEJMoa1103849 21830940 PMC3387277 · DOI · Paper page
  12. [15]Stein S. Ott M.G. Schultze-Strasser S. Jauch A. Burwinkel B. Kinner A. Schmidt M. Kramer A. Schwable J. Glimm H. Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease Nat. Med. 2010 16 198 204 10.1038/nm.2088 20098431 · DOI
  13. [16]Naldini L. Blomer U. Gallay P. Ory D. Mulligan R. Gage F.H. Verma I.M. Trono D. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector Science 1996 272 263 267 8602510
  14. [17]Zufferey R. Dull T. Mandel R.J. Bukovsky A. Quiroz D. Naldini L. Trono D. Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery J. Virol. 1998 72 9873 9880 9811723 PMC110499
  15. [18]Zufferey R. Nagy D. Mandel R.J. Naldini L. Trono D. Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo Nat. Biotechnol. 1997 15 871 875 10.1038/nbt0997-871 9306402 · DOI · Paper page
  16. [19]Dull T. Zufferey R. Kelly M. Mandel R.J. Nguyen M. Trono D. Naldini L. A third-generation lentivirus vector with a conditional packaging system J. Virol. 1998 72 8463 8471 9765382 PMC110254
  17. [20]Aiken C. Pseudotyping human immunodeficiency virus type 1 (HIV-1) by the glycoprotein of vesicular stomatitis virus targets HIV-1 entry to an endocytic pathway and suppresses both the requirement for Nef and the sensitivity to cyclosporin A J. Virol. 1997 71 5871 5877 9223476 PMC191842
  18. [21]Braaten D. Luban J. Cyclophilin A regulates HIV-1 infectivity, as demonstrated by gene targeting in human T cells EMBO J. 2001 20 1300 1309 10.1093/emboj/20.6.1300 11250896 PMC145517 · DOI
  19. [23]Luban J. Human immunodeficiency virus type 1 gag protein binds to cyclophilin A and B Cell 1993 73 1067 1078 10.1016/0092-8674(93)90637-6 8513493 · DOI
  20. [24]Luban J. Absconding with the chaperone: Essential cyclophilin-Gag interaction in HIV-1 virions Cell 1996 87 1157 1159 10.1016/S0092-8674(00)81811-5 8980222 · DOI
  21. [25]Zhang S. Joseph G. Pollok K. Berthoux L. Sastry L. Luban J. Cornetta K. The role of cyclophilin A and G2 cell cycle arrest in lentiviral gene transfer Mol. Ther. 2006 14 546 554 10.1016/j.ymthe.2006.05.022 16901758 · DOI
  22. [26]Kalpana G.V. Marmon S. Wang W. Crabtree G.R. Goff S.P. Binding and stimulation of HIV-1 integrase by a human homolog of yeast transcription factor SNF5 Science 1994 266 2002 2006 7801128
  23. [27]Yung E. Sorin M. Pal A. Craig E. Morozov A. Delattre O. Kappes J. Ott D. Kalpana G.V. Inhibition of HIV-1 virion production by a transdominant mutant of integrase interactor 1 Nat. Med. 2001 7 920 926 10.1038/90959 11479624 · DOI
  24. [28]Yung E. Sorin M. Wang E.J. Perumal S. Ott D. Kalpana G.V. Specificity of interaction of INI1/hSNF5 with retroviral integrases and its functional significance J. Virol. 2004 78 2222 2231 10.1128/JVI.78.5.2222-2231.2004 14963118 PMC369229 · DOI
  25. [29]Barry S.C. Harder B. Brzezinski M. Flint L.Y. Seppen J. Osborne W.R. Lentivirus vectors encoding both central polypurine tract and posttranscriptional regulatory element provide enhanced transduction and transgene expression Hum. Gene Ther. 2001 12 1103 1108 10.1089/104303401750214311 11399231 · DOI
  26. [30]Van Maele B. de Rijck J. de Clercq E. Debyser Z. Impact of the central polypurine tract on the kinetics of human immunodeficiency virus type 1 vector transduction J. Virol. 2003 77 4685 4694 10.1128/JVI.77.8.4685-4694.2003 12663775 PMC152151 · DOI
  27. [31]Zufferey R. Donello J.E. Trono D. Hope T.J. Woodchuck hepatitis virus posttranscriptional regulatory element enhances expression of transgenes delivered by retroviral vectors J. Virol. 1999 73 2886 2892 10074136 PMC104046
  28. [32]Dupuy F.P. Mouly E. Mesel-Lemoine M. Morel C. Abriol J. Cherai M. Baillou C. Negre D. Cosset F.L. Klatzmann D. Lentiviral transduction of human hematopoietic cells by HIV-1- and SIV-based vectors containing a bicistronic cassette driven by various internal promoters J. Gene Med. 2005 7 1158 1171 10.1002/jgm.769 15880619 · DOI
  29. [33]Miyoshi H. Blomer U. Takahashi M. Gage F.H. Verma I.M. Development of a self-inactivating lentivirus vector J. Virol. 1998 72 8150 8157 9733856 PMC110156
  30. [34]Leath A. Cornetta K. Developing novel lentiviral vectors into clinical products Methods Enzymol. 2012 507 89 108 10.1016/B978-0-12-386509-0.00005-3 22365770 · DOI
  31. [36]Merten O. Charrier S. Laroudie N. Fauchille S. Dugue C. Jenny C. Audit M. Zanta-Boussif M. Chautard H. Radrizzani M. Large scale manufacture and characterisation of a lentiviral vector produced for clinical ex vivo gene therapy application Hum. Gene Ther. 2011 22 343 356 10.1089/hum.2010.060 21043787 · DOI
  32. [37]Fassati A. Goff S.P. Characterization of intracellular reverse transcription complexes of human immunodeficiency virus type 1 J. Virol. 2001 75 3626 3635 10.1128/JVI.75.8.3626-3635.2001 11264352 PMC114854 · DOI
  33. [38]Farnet C.M. Haseltine W.A. Determination of viral proteins present in the human immunodeficiency virus type 1 preintegration complex J. Virol. 1991 65 1910 1915 2002549 PMC240011
  34. [39]Miller M.D. Farnet C.M. Bushman F.D. Human immunodeficiency virus type 1 preintegration complexes: Studies of organization and composition J. Virol. 1997 71 5382 5390 9188609 PMC191777
  35. [40]Bukrinsky M.I. Sharova N. McDonald T.L. Pushkarskaya T. Tarpley W.G. Stevenson M. Association of integrase, matrix, and reverse transcriptase antigens of human immunodeficiency virus type 1 with viral nucleic acids following acute infection Proc. Natl. Acad. Sci. USA 1993 90 6125 6129 10.1073/pnas.90.13.6125 7687060 PMC46880 · DOI · Paper page
  36. [42]De Rijck J. Vandekerckhove L. Christ F. Debyser Z. Lentiviral nuclear import: A complex interplay between virus and host BioEssays 2007 29 441 451 10.1002/bies.20561 17450594 · DOI
  37. [43]Stevenson M. Portals of entry: Uncovering HIV nuclear transport pathways Trends Cell Biol. 1996 6 9 15 10.1016/0962-8924(96)81032-4 15157526 · DOI
  38. [44]Fassati A. HIV infection of non-dividing cells: A divisive problem Retrovirology 2006 3 74 10.1186/1742-4690-3-74 17067381 PMC1635064 · DOI
  39. [46]Li L. Olvera J.M. Yoder K.E. Mitchell R.S. Butler S.L. Lieber M. Martin S.L. Bushman F.D. Role of the non-homologous DNA end joining pathway in the early steps of retroviral infection EMBO J. 2001 20 3272 3281 10.1093/emboj/20.12.3272 11406603 PMC150207 · DOI
  40. [47]Folger K.R. Wong E.A. Wahl G. Capecchi M.R. Patterns of integration of DNA microinjected into cultured mammalian cells: Evidence for homologous recombination between injected plasmid DNA molecules Mol. Cell. Biol. 1982 2 1372 1387 6298598 PMC369942
  41. [48]Jeanson L. Subra F. Vaganay S. Hervy M. Marangoni E. Bourhis J. Mouscadet J.F. Effect of Ku80 depletion on the preintegrative steps of HIV-1 replication in human cells Virology 2002 300 100 108 10.1006/viro.2002.1515 12202210 · DOI
  42. [49]Kilzer J.M. Stracker T. Beitzel B. Meek K. Weitzman M. Bushman F.D. Roles of host cell factors in circularization of retroviral dna Virology 2003 314 460 467 10.1016/S0042-6822(03)00455-0 14517098 · DOI
  43. [50]Farnet C.M. Haseltine W.A. Circularization of human immunodeficiency virus type 1 DNA in vitro J. Virol. 1991 65 6942 6952 1834863 PMC250802
  44. [51]Gianni A.M. Smotkin D. Weinberg R.A. Murine leukemia virus: Detection of unintegrated double-stranded DNA forms of the provirus Proc. Natl. Acad. Sci. USA 1975 72 447 451 10.1073/pnas.72.2.447 1054828 PMC432328 · DOI
  45. [52]Jacque J.M. Stevenson M. The inner-nuclear-envelope protein emerin regulates HIV-1 infectivity Nature 2006 441 641 645 10.1038/nature04682 16680152 · DOI
  46. [53]Shank P.R. Hughes S.H. Kung H.J. Majors J.E. Quintrell N. Guntaka R.V. Bishop J.M. Varmus H.E. Mapping unintegrated avian sarcoma virus DNA: Termini of linear DNA bear 300 nucleotides present once or twice in two species of circular DNA Cell 1978 15 1383 1395 10.1016/0092-8674(78)90063-6 215324 · DOI
  47. [54]Gilboa E. Mitra S.W. Goff S. Baltimore D. A detailed model of reverse transcription and tests of crucial aspects Cell 1979 18 93 100 10.1016/0092-8674(79)90357-X 509527 · DOI · Paper page
  48. [55]Klarmann G.J. Yu H. Chen X. Dougherty J.P. Preston B.D. Discontinuous plus-strand DNA synthesis in human immunodeficiency virus type 1-infected cells and in a partially reconstituted cell-free system J. Virol. 1997 71 9259 9269 9371584 PMC230228
  49. [56]Dina D. Benz E.W. Jr. Structure of murine sarcoma virus DNA replicative intermediates synthesized in vitro J. Virol. 1980 33 377 389 6245239 PMC288554
  50. [57]Junghans R.P. Boone L.R. Skalka A.M. Products of reverse transcription in avian retrovirus analyzed by electron microscopy J. Virol. 1982 43 544 554 6180182 PMC256158
  51. [58]Kantor B. Bayer M. Ma H. Samulski J. Li C. McCown T. Kafri T. Notable reduction in illegitimate integration mediated by a PPT-deleted, nonintegrating lentiviral vector Mol. Ther. 2011 19 547 556 10.1038/mt.2010.277 21157436 PMC3048187 · DOI · Paper page
  52. [59]Ringold G.M. Yamamoto K.R. Shank P.R. Varmus H.E. Mouse mammary tumor virus DNA in infected rat cells: Characterization of unintegrated forms Cell 1977 10 19 26 10.1016/0092-8674(77)90135-0 189933 · DOI
  53. [60]Shoemaker C. Goff S. Gilboa E. Paskind M. Mitra S.W. Baltimore D. Structure of a cloned circular Moloney murine leukemia virus DNA molecule containing an inverted segment: Implications for retrovirus integration Proc. Natl. Acad. Sci. USA 1980 77 3932 3936 10.1073/pnas.77.7.3932 6449003 PMC349741 · DOI
  54. [61]Apolonia L. Waddington S.N. Fernandes C. Ward N.J. Bouma G. Blundell M.P. Thrasher A.J. Collins M.K. Philpott N.J. Stable gene transfer to muscle using non-integrating lentiviral vectors Mol. Ther. 2007 15 1947 1954 10.1038/sj.mt.6300281 17700544 · DOI · Paper page
  55. [64]Bayer M. Kantor B. Cockrell A. Ma H. Zeithaml B. Li X. McCown T. Kafri T. A large U3 deletion causes increased in vivo expression from a nonintegrating lentiviral vector Mol. Ther. 2008 16 1968 1976 10.1038/mt.2008.199 18797449 PMC2587457 · DOI · Paper page
  56. [65]Zhou H. Rainey G.J. Wong S.K. Coffin J.M. Substrate sequence selection by retroviral integrase J. Virol. 2001 75 1359 1370 10.1128/JVI.75.3.1359-1370.2001 11152509 PMC114042 · DOI
  57. [66]Hindmarsh P. Leis J. Retroviral DNA integration Microbiol. Mol. Biol. Rev. 1999 63 836 843 10585967 PMC98978
  58. [69]Craigie R. Fujiwara T. Bushman F. The IN protein of Moloney murine leukemia virus processes the viral DNA ends and accomplishes their integration in vitro Cell 1990 62 829 837 10.1016/0092-8674(90)90126-Y 2167180 · DOI · Paper page
  59. [70]Katz R.A. Merkel G. Kulkosky J. Leis J. Skalka A.M. The avian retroviral IN protein is both necessary and sufficient for integrative recombination in vitro Cell 1990 63 87 95 10.1016/0092-8674(90)90290-U 2170022 · DOI · Paper page
  60. [71]Mizuuchi K. Polynucleotidyl transfer reactions in transpositional DNA recombination J. Biol. Chem. 1992 267 21273 21276 1383220
  61. [72]Zhu K. Dobard C. Chow S.A. Requirement for integrase during reverse transcription of human immunodeficiency virus type 1 and the effect of cysteine mutations of integrase on its interactions with reverse transcriptase J. Virol. 2004 78 5045 5055 10.1128/JVI.78.10.5045-5055.2004 15113886 PMC400327 · DOI
  62. [73]Gallay P. Hope T. Chin D. Trono D. HIV-1 infection of nondividing cells through the recognition of integrase by the importin/karyopherin pathway Proc. Natl. Acad. Sci. USA 1997 94 9825 9830 10.1073/pnas.94.18.9825 9275210 PMC23276 · DOI
  63. [75]Saenz D.T. Loewen N. Peretz M. Whitwam T. Barraza R. Howell K.G. Holmes J.M. Good M. Poeschla E.M. Unintegrated lentivirus DNA persistence and accessibility to expression in nondividing cells: Analysis with class I integrase mutants J. Virol. 2004 78 2906 2920 10.1128/JVI.78.6.2906-2920.2004 14990709 PMC353756 · DOI
  64. [76]Wiskerchen M. Muesing M.A. Human immunodeficiency virus type 1 integrase: Effects of mutations on viral ability to integrate, direct viral gene expression from unintegrated viral DNA templates, and sustain viral propagation in primary cells J. Virol. 1995 69 376 386 7983732 PMC188585
  65. [78]Kulkosky J. Jones K.S. Katz R.A. Mack J.P. Skalka A.M. Residues critical for retroviral integrative recombination in a region that is highly conserved among retroviral/retrotransposon integrases and bacterial insertion sequence transposases Mol. Cell. Biol. 1992 12 2331 2338 1314954 PMC364405
  66. [79]Shibagaki Y. Chow S.A. Central core domain of retroviral integrase is responsible for target site selection J. Biol. Chem. 1997 272 8361 8369 10.1074/jbc.272.13.8361 9079660 · DOI · Paper page
  67. [80]Nightingale S.J. Hollis R.P. Pepper K.A. Petersen D. Yu X.J. Yang C. Bahner I. Kohn D.B. Transient gene expression by nonintegrating lentiviral vectors Mol. Ther. 2006 13 1121 1132 10.1016/j.ymthe.2006.01.008 16556511 · DOI · Paper page
  68. [81]Leavitt A.D. Robles G. Alesandro N. Varmus H.E. Human immunodeficiency virus type 1 integrase mutants retain in vitro integrase activity yet fail to integrate viral DNA efficiently during infection J. Virol. 1996 70 721 728 8551608 PMC189872
  69. [82]Brown H.E. Chen H. Engelman A. Structure-based mutagenesis of the human immunodeficiency virus type 1 DNA attachment site: Effects on integration and cDNA synthesis J. Virol. 1999 73 9011 9020 10516007 PMC112933
  70. [83]Masuda T. Planelles V. Krogstad P. Chen I.S. Genetic analysis of human immunodeficiency virus type 1 integrase and the U3 att site: Unusual phenotype of mutants in the zinc finger-like domain J. Virol. 1995 69 6687 6696 7474078 PMC189578
  71. [85]Gaur M. Leavitt A.D. Mutations in the human immunodeficiency virus type 1 integrase D,D(35)E motif do not eliminate provirus formation J. Virol. 1998 72 4678 4685 9573231 PMC109991
  72. [86]Leavitt A.D. Shiue L. Varmus H.E. Site-directed mutagenesis of HIV-1 integrase demonstrates differential effects on integrase functions in vitro J. Biol. Chem. 1993 268 2113 2119 8420982
  73. [87]Nakajima N. Lu R. Engelman A. Human immunodeficiency virus type 1 replication in the absence of integrase-mediated dna recombination: Definition of permissive and nonpermissive T-cell lines J. Virol. 2001 75 7944 7955 10.1128/JVI.75.17.7944-7955.2001 11483739 PMC115038 · DOI
  74. [88]Matrai J. Chuah M.K. VandenDriessche T. Recent advances in lentiviral vector development and applications Mol. Ther. 2010 18 477 490 10.1038/mt.2009.319 20087315 PMC2839421 · DOI
  75. [89]Yanez-Munoz R.J. Balaggan K.S. MacNeil A. Howe S.J. Schmidt M. Smith A.J. Buch P. MacLaren R.E. Anderson P.N. Barker S.E. Effective gene therapy with nonintegrating lentiviral vectors Nat. Med. 2006 12 348 353 16491086
  76. [90]Koyama T. Sun B. Tokunaga K. Tatsumi M. Ishizaka Y. DNA damage enhances integration of HIV-1 into macrophages by overcoming integrase inhibition Retrovirology 2013 10 21 10.1186/1742-4690-10-21 23432899 PMC3605128 · DOI
  77. [93]Coutant F. Frenkiel M.P. Despres P. Charneau P. Protective antiviral immunity conferred by a nonintegrative lentiviral vector-based vaccine PLoS One 2008 3 e3973 10.1371/journal.pone.0003973 19096527 PMC2600612 · DOI · Paper page
  78. [94]Vargas J. Jr. Gusella G.L. Najfeld V. Klotman M.E. Cara A. Novel integrase-defective lentiviral episomal vectors for gene transfer Hum. Gene Ther. 2004 15 361 372 10.1089/104303404322959515 15053861 · DOI
  79. [95]Vargas J. Jr. Klotman M.E. Cara A. Conditionally replicating lentiviral-hybrid episomal vectors for suicide gene therapy Antivir. Res. 2008 80 288 294 10.1016/j.antiviral.2008.06.015 18647620 · DOI
  80. [96]Hacein-Bey-Abina S. Garrigue A. Wang G.P. Soulier J. Lim A. Morillon E. Clappier E. Caccavelli L. Delabesse E. Beldjord K. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1 J. Clin. Investig. 2008 118 3132 3142 10.1172/JCI35700 18688285 PMC2496963 · DOI · Paper page
  81. [97]Hacein-Bey-Abina S. Von Kalle C. Schmidt M. McCormack M.P. Wulffraat N. Leboulch P. Lim A. Osborne C.S. Pawliuk R. Morillon E. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1 Science 2003 302 415 419 10.1126/science.1088547 14564000 · DOI · Paper page
  82. [98]Howe S.J. Mansour M.R. Schwarzwaelder K. Bartholomae C. Hubank M. Kempski H. Brugman M.H. Pike-Overzet K. Chatters S.J. de Ridder D. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients J. Clin. Investig. 2008 118 3143 3150 10.1172/JCI35798 18688286 PMC2496964 · DOI · Paper page
  83. [99]Boztug K. Schmidt M. Schwarzer A. Banerjee P.P. Diez I.A. Dewey R.A. Bohm M. Nowrouzi A. Ball C.R. Glimm H. Stem-cell gene therapy for the Wiskott-Aldrich syndrome N. Engl. J. Med. 2010 363 1918 1927 10.1056/NEJMoa1003548 21067383 PMC3064520 · DOI · Paper page
  84. [100]Persons D.A. Baum C. Solving the problem of gamma-retroviral vectors containing long terminal repeats Mol. Ther. 2011 19 229 231 10.1038/mt.2010.305 21289636 PMC3034864 · DOI
  85. [101]Montini E. Cesana D. Schmidt M. Sanvito F. Ponzoni M. Bartholomae C. Sergi Sergi L. Benedicenti F. Ambrosi A. Di Serio C. Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration Nat. Biotechnol. 2006 24 687 696 10.1038/nbt1216 16732270 · DOI
  86. [102]Ramezani A. Hawley T.S. Hawley R.G. Combinatorial incorporation of enhancer-blocking components of the chicken beta-globin 5'HS4 and human T-cell receptor alpha/delta BEAD-1 insulators in self-inactivating retroviral vectors reduces their genotoxic potential Stem Cells 2008 26 3257 3266 10.1634/stemcells.2008-0258 18787211 PMC2605779 · DOI
  87. [103]Ryu B.Y. Evans-Galea M.V. Gray J.T. Bodine D.M. Persons D.A. Nienhuis A.W. An experimental system for the evaluation of retroviral vector design to diminish the risk for proto-oncogene activation Blood 2008 111 1866 1875 10.1182/blood-2007-04-085506 17991809 PMC2234041 · DOI
  88. [105]Zhou S. Mody D. DeRavin S.S. Hauer J. Lu T. Ma Z. Hacein-Bey Abina S. Gray J.T. Greene M.R. Cavazzana-Calvo M. A self-inactivating lentiviral vector for SCID-X1 gene therapy that does not activate LMO2 expression in human T cells Blood 2010 116 900 908 10.1182/blood-2009-10-250209 20457870 PMC2924228 · DOI · Paper page
  89. [106]Schambach A. Zychlinski D. Ehrnstroem B. Baum C. Biosafety features of lentiviral vectors Hum. Gene Ther. 2013 24 132 142 10.1089/hum.2012.229 23311447 PMC3581032 · DOI · Paper page
  90. [107]Berger G. Turpin J. Cordeil S. Tartour K. Nguyen X.N. Mahieux R. Cimarelli A. Functional analysis of the relationship between Vpx and the restriction factor SAMHD1 J. Biol. Chem. 2012 287 41210 41217 10.1074/jbc.M112.403816 23076149 PMC3510820 · DOI
  91. [108]Goldstone D.C. Ennis-Adeniran V. Hedden J.J. Groom H.C. Rice G.I. Christodoulou E. Walker P.A. Kelly G. Haire L.F. Yap M.W. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase Nature 2011 480 379 382 10.1038/nature10623 22056990 · DOI
  92. [110]Laguette N. Sobhian B. Casartelli N. Ringeard M. Chable-Bessia C. Segeral E. Yatim A. Emiliani S. Schwartz O. Benkirane M. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx Nature 2011 474 654 657 10.1038/nature10117 21613998 PMC3595993 · DOI · Paper page
  93. [111]Berger G. Goujon C. Darlix J.L. Cimarelli A. SIVMAC Vpx improves the transduction of dendritic cells with nonintegrative HIV-1-derived vectors Gene Ther. 2009 16 159 163 10.1038/gt.2008.128 18668143 · DOI
  94. [112]Negri D.R. Rossi A. Blasi M. Michelini Z. Leone P. Chiantore M.V. Baroncelli S. Perretta G. Cimarelli A. Klotman M.E. Simian immunodeficiency virus-Vpx for improving integrase defective lentiviral vector-based vaccines Retrovirology 2012 9 69 10.1186/1742-4690-9-69 22913641 PMC3468359 · DOI
  95. [113]Suwanmanee T. Hu G. Gui T. Bartholomae C.C. Kutschera I. von Kalle C. Schmidt M. Monahan P.E. Kafri T. Integration-deficient lentiviral vectors expressing codon-optimized R338L human FIX restore normal hemostasis in hemophilia B mice Mol. Ther. 2013 10.1038/mt.2013.188 PMC3944325 23941813 · DOI
  96. [115]Pelascini L.P. Janssen J.M. Goncalves M.A. Histone deacetylase inhibition activates transgene expression from integration-defective lentiviral vectors in dividing and non-dividing cells Hum. Gene Ther. 2013 24 78 96 10.1089/hum.2012.069 23140481 PMC3555116 · DOI
  97. [116]Coutant F. Sanchez David R.Y. Felix T. Boulay A. Caleechurn L. Souque P. Thouvenot C. Bourgouin C. Beignon A.S. Charneau P. A nonintegrative lentiviral vector-based vaccine provides long-term sterile protection against malaria PLoS One 2012 7 e48644 10.1371/journal.pone.0048644 23133649 PMC3487763 · DOI · Paper page
  98. [117]Deng Y. Guan J. Wen B. Zhu N. Chen H. Song J. Yang Y. Wang Y. Tan W. Induction of broadly neutralising HCV antibodies in mice by integration-deficient lentiviral vector-based pseudotyped particles PLoS One 2013 8 e62684 23626846 PMC3633868
  99. [118]Grasso F. Negri D.R. Mochi S. Rossi A. Cesolini A. Giovannelli A. Chiantore M.V. Leone P. Giorgi C. Cara A. Successful therapeutic vaccination with integrase defective lentiviral vector expressing nononcogenic human papillomavirus E7 protein Int. J. Cancer 2012 132 335 344 22700466
  100. [119]Hu B. Dai B. Wang P. Vaccines delivered by integration-deficient lentiviral vectors targeting dendritic cells induces strong antigen-specific immunity Vaccine 2010 28 6675 6683 10.1016/j.vaccine.2010.08.012 20709004 PMC2956406 · DOI · Paper page
  101. [120]Karwacz K. Mukherjee S. Apolonia L. Blundell M.P. Bouma G. Escors D. Collins M.K. Thrasher A.J. Nonintegrating lentivector vaccines stimulate prolonged T-cell and antibody responses and are effective in tumor therapy J. Virol. 2009 83 3094 3103 10.1128/JVI.02519-08 19176629 PMC2655594 · DOI · Paper page
  102. [123]Papapetrou E.P. Sadelain M. Generation of transgene-free human induced pluripotent stem cells with an excisable single polycistronic vector Nat. Protocols 2011 6 1251 1273 10.1038/nprot.2011.374 21886095 · DOI
  103. [124]Holmes-Son M.L. Chow S.A. Correct integration mediated by integrase-LexA fusion proteins incorporated into HIV-1 Mol. Ther. 2002 5 360 370 10.1006/mthe.2002.0559 11945062 · DOI
  104. [125]Tan W. Dong Z. Wilkinson T.A. Barbas C.F. 3rd Chow S.A. Human immunodeficiency virus type 1 incorporated with fusion proteins consisting of integrase and the designed polydactyl zinc finger protein E2C can bias integration of viral DNA into a predetermined chromosomal region in human cells J. Virol. 2006 80 1939 1948 10.1128/JVI.80.4.1939-1948.2006 16439549 PMC1367172 · DOI
  105. [126]Moldt B. Staunstrup N.H. Jakobsen M. Yanez-Munoz R.J. Mikkelsen J.G. Genomic insertion of lentiviral DNA circles directed by the yeast Flp recombinase BMC Biotechnol. 2008 8 60 10.1186/1472-6750-8-60 18691430 PMC2538528 · DOI · Paper page
  106. [127]Vink C.A. Gaspar H.B. Gabriel R. Schmidt M. McIvor R.S. Thrasher A.J. Qasim W. Sleeping beauty transposition from nonintegrating lentivirus Mol. Ther. 2009 17 1197 1204 10.1038/mt.2009.94 19417741 PMC2835211 · DOI
  107. [128]Okada Y. Ueshin Y. Hasuwa H. Takumi K. Okabe M. Ikawa M. Targeted gene modification in mouse ES cells using integrase-defective lentiviral vectors Genesis 2009 47 217 223 10.1002/dvg.20469 19208434 · DOI
  108. [129]Lombardo A. Genovese P. Beausejour C.M. Colleoni S. Lee Y.L. Kim K.A. Ando D. Urnov F.D. Galli C. Gregory P.D. Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery Nat. Biotechnol. 2007 25 1298 1306 10.1038/nbt1353 17965707 · DOI · Paper page
  109. [130]Lombardo A. Cesana D. Genovese P. di Stefano B. Provasi E. Colombo D.F. Neri M. Magnani Z. Cantore A. Lo Riso P. Site-specific integration and tailoring of cassette design for sustainable gene transfer Nat. Methods 2011 8 861 869 10.1038/nmeth.1674 21857672 · DOI
  110. [132]Osborn M.J. Starker C.G. McElroy A.N. Webber B.R. Riddle M.J. Xia L. DeFeo A.P. Gabriel R. Schmidt M. von Kalle C. TALEN-based gene correction for epidermolysis bullosa Mol. Ther. 2013 21 1151 1159 10.1038/mt.2013.56 23546300 PMC3677309 · DOI · Paper page
  111. [133]Cantore A. Nair N. Della Valle P. di Matteo M. Matrai J. Sanvito F. Brombin C. di Serio C. D’Angelo A. Chuah M. Hyperfunctional coagulation factor IX improves the efficacy of gene therapy in hemophilic mice Blood 2012 120 4517 4520 10.1182/blood-2012-05-432591 23043073 · DOI · Paper page
  112. [135]Michelini Z. Negri D.R. Baroncelli S. Spada M. Leone P. Bona R. Klotman M.E. Cara A. Development and use of SIV-based Integrase defective lentiviral vector for immunization Vaccine 2009 27 4622 4629 10.1016/j.vaccine.2009.05.070 19523909 PMC2754741 · DOI · Paper page
  113. [136]Daenthanasanmak A. Salguero G. Borchers S. Figueiredo C. Jacobs R. Sundarasetty B.S. Schneider A. Schambach A. Eiz-Vesper B. Blasczyk R. Integrase-defective lentiviral vectors encoding cytokines induce differentiation of human dendritic cells and stimulate multivalent immune responses in vitro and in vivo Vaccine 2012 30 5118 5131 10.1016/j.vaccine.2012.05.063 22691433 · DOI
  114. [138]Takahashi K. Tanabe K. Ohnuki M. Narita M. Ichisaka T. Tomoda K. Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors Cell 2007 131 861 872 10.1016/j.cell.2007.11.019 18035408 · DOI · Paper page
  115. [139]Wernig M. Meissner A. Foreman R. Brambrink T. Ku M. Hochedlinger K. Bernstein B.E. Jaenisch R. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state Nature 2007 448 318 324 10.1038/nature05944 17554336 · DOI
  116. [140]Okita K. Ichisaka T. Yamanaka S. Generation of germline-competent induced pluripotent stem cells Nature 2007 448 313 317 10.1038/nature05934 17554338 · DOI
  117. [141]Soldner F. Hockemeyer D. Beard C. Gao Q. Bell G.W. Cook E.G. Hargus G. Blak A. Cooper O. Mitalipova M. Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors Cell 2009 136 964 977 10.1016/j.cell.2009.02.013 19269371 PMC2787236 · DOI
  118. [142]Stadtfeld M. Nagaya M. Utikal J. Weir G. Hochedlinger K. Induced pluripotent stem cells generated without viral integration Science 2008 322 945 949 10.1126/science.1162494 18818365 PMC3987909 · DOI · Paper page
  119. [143]Yu J. Hu K. Smuga-Otto K. Tian S. Stewart R. Sukvin II Thomson J.A. Human induced pluripotent stem cells free of vector and transgene sequences Science 2009 324 797 801 10.1126/science.1172482 19325077 PMC2758053 · DOI · Paper page
  120. [144]Goulaouic H. Chow S.A. Directed integration of viral DNA mediated by fusion proteins consisting of human immunodeficiency virus type 1 integrase and Escherichia coli LexA protein J. Virol. 1996 70 37 46 8523550 PMC189785
  121. [145]Holmes-Son M.L. Chow S.A. Integrase-lexA fusion proteins incorporated into human immunodeficiency virus type 1 that contains a catalytically inactive integrase gene are functional to mediate integration J. Virol. 2000 74 11548 11556 10.1128/JVI.74.24.11548-11556.2000 11090152 PMC112435 · DOI
  122. [146]Moldt B. Miskey C. Staunstrup N.H. Gogol-Doring A. Bak R.O. Sharma N. Mates L. Izsvak Z. Chen W. Ivics Z. Comparative genomic integration profiling of Sleeping Beauty transposons mobilized with high efficacy from integrase-defective lentiviral vectors in primary human cells Mol. Ther. 2011 19 1499 1510 10.1038/mt.2011.47 21468003 PMC3149173 · DOI
  123. [147]Calin G.A. Croce C.M. MicroRNA signatures in human cancers Nat. Rev. Cancer 2006 6 857 866 10.1038/nrc1997 17060945 · DOI
  124. [148]Ventura A. Jacks T. MicroRNAs and cancer: Short RNAs go a long way Cell 2009 136 586 591 10.1016/j.cell.2009.02.005 19239879 PMC3910108 · DOI
  125. [149]Esquela-Kerscher A. Trang P. Wiggins J.F. Patrawala L. Cheng A. Ford L. Weidhaas J.B. Brown D. Bader A.G. Slack F.J. The let-7 microRNA reduces tumor growth in mouse models of lung cancer Cell Cycle 2008 7 759 764 10.4161/cc.7.6.5834 18344688 · DOI
  126. [150]Kumar M.S. Erkeland S.J. Pester R.E. Chen C.Y. Ebert M.S. Sharp P.A. Jacks T. Suppression of non-small cell lung tumor development by the let-7 microRNA family Proc. Natl. Acad. Sci. USA 2008 105 3903 3908 18308936 PMC2268826
  127. [151]Hsu S.H. Wang B. Kota J. Yu J. Costinean S. Kutay H. Yu L. Bai S. La Perle K. Chivukula R.R. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver J. Clin. Investig. 2012 122 2871 2883 10.1172/JCI63539 22820288 PMC3408748 · DOI
  128. [152]Kota J. Chivukula R.R. O’Donnell K.A. Wentzel E.A. Montgomery C.L. Hwang H.W. Chang T.C. Vivekanandan P. Torbenson M. Clark K.R. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model Cell 2009 137 1005 1017 10.1016/j.cell.2009.04.021 19524505 PMC2722880 · DOI

Cited by

Sorted by citations

Authors
Shaw, A., & Cornetta, K.
Affiliations
Indiana University School of Medicine (US)
Corresponding author
Cornetta, Kenneth
ORCID
Cornetta, Kenneth
Venue
Biomedicines
Publisher
MDPI AG
Published
2014-01-27
Volume
2
Issue
1
Pages
14-35
ISSN
2227-9059 (ISSN-L)
DOI
10.3390/biomedicines2010014
PMC
PMC5423482
OpenAlex
W2076286186
Cited by
60
References
23
Citations by year
2026: 4 · 2025: 7 · 2024: 7 · 2023: 3 · 2022: 8 · 2021: 8 · 2020: 5 · 2019: 2 · 2018: 3 · 2017: 5 · 2016: 5 · 2015: 2 · 2014: 1
FWCI
0.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomedicines (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
  • PMC
Funders
National Center for Research Resources (P40RR024928)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
Keywords
lentiviral vectors, long terminal repeat, transient expression, gene therapy safety, hematopoietic cells, cancer gene therapy, vaccination, gene disruption, cellular reprogramming

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review