State-of-the-art lentiviral vectors for research use: Risk assessment and biosafety recommendations

Current Gene Therapy

Volumn 9, Issue 6, 2009, Pages 459-474

  Pauwels, Katia ^a   Gijsbers, Rik ^b   Toelen, Jaan ^b   Schambach, Axel ^c   Willard Gallo, Karen ^d   Verheust, Céline ^a   Debyser, Zeger ^b   Herman, Philippe ^a  

^a SCIENTIFIC INSTITUTE OF PUBLIC HEALTH   (Belgium)

^b DEPARTMENT OF PHARMACEUTICAL AND PHARMACOLOGICAL SCIENCES   (Belgium)

^c HANNOVER MEDICAL SCHOOL   (Germany)

^d JULES BORDET INSTITUTE   (Belgium)

Author keywords

Biosafety; Gene transfer; Guidelines; HIV 1 derived vector; Lentivirus; Split packaging; Vector design; Vector production

Indexed keywords

LENTIVIRUS VECTOR;

BIOSAFETY; CELL CULTURE; CLINICAL EFFECTIVENESS; CLINICAL TRIAL; GENE SEQUENCE; GENE TRANSFER; GENE VECTOR; GENETIC RECOMBINATION; GENETIC TRANSDUCTION; HOMOLOGOUS RECOMBINATION; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; INFECTION CONTROL; LABORATORY INFECTION; LABORATORY PERSONNEL; NONHUMAN; OCCUPATIONAL EXPOSURE; PRACTICE GUIDELINE; PROCESS OPTIMIZATION; PSEUDOTYPING; REVIEW; RISK ASSESSMENT; RISK REDUCTION; VIRAL GENE DELIVERY SYSTEM; VIRUS GENE; VIRUS REPLICATION;

HUMAN IMMUNODEFICIENCY VIRUS 1; LENTIVIRUS;

EID: 73449123732     PISSN: 15665232     EISSN: None     Source Type: Journal    
DOI: 10.2174/156652309790031120     Document Type: Review

References (132)

1. WHO, Laboratory Biosafety Manual, 2004, 3rd ed. Available at: http://www.who.int/csr/resources/publications/biosafety/WHO-CDS-CSR-LYO-2004-11/ en/
2. OSHA (US). Occupational Safety and health Administration. Available at http://www.osha.gov/
3. Directive 2000/54/EC of the European Parliament and of the Council of 18 September 2000 on the protection of workers from risks related to exposure to biological agents at work. OJ L 262, 17/10/2000 P. 0021-45.
4. Directive 98/81/EC of 26 October 1998 amending Directive 90/219/EEC on the contained use of genetically modified microorganisms. OJ L 330, 05/12/1998 P. 0013-31.
5. Directive 2001/18/EC of the European Parliament and of the Council of 21 March 2001 on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EEC. OJ L 106, 17/04/2001, P. 0001-39.
6. Food and Drug Administration (FDA). Center for Biologics Evaluation and research. Available at http://www.fda.gov/ BiologicsBloodVaccines/ CellularGeneTherapyProducts/default.htm
7. NIH guidelines (US), National Institute of Health. Available at http://oba.od.nih.gov/rdna/nih-guidelines-oba.html
8. European Agency for the Evaluation of Medicinal Products (EMEA). Available at http://www.emea.eu.int
9. Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing an European Medicines Agency (OJ L 136, 30.04.2004, p.1)
10. Chong H, Starkey W, Vile RG. A replication-competent retrovirus arising from a split-function packaging cell line was generated by recombination events between the vector, one of the packaging constructs, and endogenous retroviral sequences. J Virol 1998; 72(4): 2663-70.
11. Garrett E, Miller AR, Goldman JM, Apperley JF, Melo JV. Characterization of recombination events leading to the production of an ecotropic replication-competent retrovirus in a GP+envAM12-derived producer cell line. Virology 2000; 266(1): 170-9.
12. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy SCID-X1. Science 2003; 302: 415-9.
13. Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest 2008; 118(9): 3132-42.
14. Howe SJ, Mansour MR, Schwarzwaelder K, et al. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Invest 2008; 118(9): 3143-50.
15. Li Z, Düllmann J, Schiedlmeier B, et al. Murine leukemia induced by retroviral gene marking. Science 2002; 296(5567): 497.
16. Themis M, Waddington SN, Schmidt M, et al. Oncogenesis following delivery of a nonprimate lentiviral gene therapy vector to fetal and neonatal mice. Mol Ther 2005; 2(4): 763-71.
17. Bank A, Dorazio R, Leboulch P. A phase I/II clinical trial of betaglobin gene therapy for beta-thalassemia. Ann N Y Acad Sci USA 2005; 1054:308-16.
18. Agence française de sécurité sanitaire des produits de santé (afssaps). Available at : http://www.afssaps.fr/Infos-de- securite/ Pointsd-information-Points-d-etape/Essai-clinique-de-therapie- geniquedans-les-hemoglobinopathies-Observation-biologique-chez-unpatient-traite [Accessed 26 August 2009]. See also Philippe Lebouch, oral presentation, ASGT 2009.
19. Sullivan RJ, Pantanowitz L, Casper C, Stebbing J, Dezube BJ. HIV/AIDS: epidemiology, pathophysiology, and treatment of Kaposi sarcoma-associated herpesvirus disease: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease. Clin Infect Dis 2008; 47(9): 1209-15. Review.
20. Carbone A, Cesarman E, Spina M, Gloghini A, Schulz TF. HIV-associated lymphomas and gamma-herpesviruses. Blood 2009; 113(6): 1213-24.
21. Herndier BG, Shiramizu BT, Jewett NE, Aldape KD, Reyes GR, McGrath MS. Acquired immunodeficiency syndrome-associated Tcell lymphoma: evidence for human immunodeficiency virus type 1-associated T-cell transformation. Blood 1992; 79(7): 1768-74.
22. Mack KD, Wei R, Herndier B, et al. HIV insertional characteristics of the protooncogene c-fes in AIDS associated lymphomagenesis. J AIDS 1997; 14: A44.
23. Shiramizu B, Herndier BG, McGrath MS. Identification of a common clonal human immunodeficiency virus integration site in human immunodeficiency virus-associated lymphomas. Cancer Res 1994; 54(8): 2069-72.
24. Han Y, Lassen K, Monie D, et al. Resting CD4+ T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals carry integrated HIV-1 genomes within actively transcribed host genes. J Virol 2004; 78(12): 6122-33.
25. Liu H, Dow EC, Arora R, et al. Integration of human immunodeficiency virus type 1 in untreated infection occurs preferentially within genes. J Virol 2006; 80(15): 7765-8.
26. Schröder AR, Shinn P, Chen H, Berry C, Ecker JR, Bushman F. HIV-1 integration in the human genome favors active genes and local hotspots. Cell 2002; 110: 521-9.
27. Vincent KA, York-Higgins D, Quiroga M, Brown PO. Host sequences flanking the HIV provirus. Nucleic Acids Res 1990; 18(20): 6045-7.
28. Wellensiek BP, Ramakrishnan R, Sundaravaradan V, Mehta R, Harris DT, Ahmad N. Differential HIV-1 integration targets more actively transcribed host genes in neonatal than adult blood mono-nuclear cells. Virology 2009; 385(1): 28-38.
29. Wu X, Li Y, Crise B, Burgess SM. Transcription start regions in the human genome are favored targets for MLV integration. Science 2003; 13: 1749-51.
30. Elleder D, Pavlícek A, Paces J, Hejnar J. Preferential integration of human immunodeficiency virus type 1 into genes, cytogenetic R bands and GC-rich DNA regions: insight from the human genome sequence. FEBS Lett 2002; 517(1-3): 285-6.
31. Mitchell RS, Beitzel BF, Schroder AR, et al. Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol 2004; 2(8): E234.
32. Stevens SW, Griffith JD. Sequence analysis of the human DNA flanking sites of human immunodeficiency virus type 1 integration. J Virol 1996; 70(9): 6459-62.
33. Vijaya S, Steffen DL, Robinson HL. Acceptor sites for retroviral integrations map near DNase I-hypersensitive sites in chromatin. J Virol 1986; 60(2): 683-92.
34. Van Maele B, Busschots K, Vandekerckhove L, Christ F, Debyser Z. Cellular co-factors of HIV-1 integration. Trends Biochem Sci 2006; 31(2): 98-105.
35. Ciuffi A. Mechanisms governing lentivirus integration site selection. Curr Gene Ther 2008; 8(6): 419-29.
36. Bushman F, Lewinski M, Ciuffi A, et al. Genomewide analysis of retroviral DNA integration. Nat Rev Microbiol 2005; 3: 848-58.
37. Cattoglio C, Facchini G, Sartori D, et al. Hot spots of retroviral integration in human CD34+ hematopoietic cells. Blood 2007; 110(6): 1770-8.
38. Montini E, Cesana D, Schmidt M, et al. The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy. J Clin Invest 2009; 119: 964-75.
39. Modlich U, Navarro S, Zychlinski D, et al. Insertional transformation of hematopoietic cells by self-inactivating lentiviral and gammaretroviral vectors. Mol Ther 2009; [Epub ahead of print].
40. Modlich U, Baum C. Preventing and exploiting the oncogenic potential of integrating gene vectors. J Clin Invest 2009; 119(4): 755-8.
41. Bokhoven M, Stephen SL, Knight S, et al. Insertional gene activation by lentiviral and gammaretroviral vectors. J Virol 2009; 83(1): 283-94.
42. Evans JT, Garcia JV. Lentivirus vector mobilization and spread by human immunodeficiency virus. Hum Gene Ther 2000; 11: 2331-9.
43. Klimatcheva E, Planelles V, Day SL, Fulreader F, Renda MJ, Rosenblatt J. Defective lentiviral vectors are efficiently trafficked by HIV-1 and inhibit its replication. Mol Ther 2001; 3(6): 928-39.
44. Levine BL, Humeau LM, Boyer J, et al. Gene transfer in humans using a conditionally replicating lentiviral vector. Proc Natl Acad Sci USA 2006; 103(46):17372-7.
45. Burns JC, Friedmann T, Driever W, Burrascano M, Yee JK. Vesicular stomatitis virus G glycoprotein pseudotyped retroviral vectors: concentration to very high titer and efficient gene transfer into mammalian and nonmammalian cells. Proc Natl Acad Sci USA 1993; 90: 8033-7.
46. DePolo NJ, Reed JD, Sheridan PL, et al. VSV-G pseudotyped lentiviral vector particles produced in human cells are inactivated by human serum. Mol Ther 2000; 2: 218-22.
47. Pichlmair A, Diebold SS, Gschmeissner S, et al. Tubulovesicular structures within vesicular stomatitis virus G protein-pseudotyped lentiviral vector preparations carry DNA and stimulate antiviral responses via Toll-like receptor 9. J Virol 2007; 81(2): 539-47.
48. Hanawa H, Kelly PF, Nathwani AC, et al. Comparison of various envelope proteins for their ability to pseudotype lentiviral vectors and transduce primitive hematopoietic cells from human blood. Mol Ther 2002; 5: 242-51.
49. Watson DJ, Kobinger GP, Passini MA, et al. Targeted transduction patterns in the mouse brain by lentivirus vectors pseudotyped with VSV, Ebola, Mokola, LCMV, or MuLV envelope proteins. Mol Ther 2002; 5: 528-37.
50. Schambach A, Galla M, Modlich U, et al. Lentiviral vectors pseudotyped with murine ecotropic envelope: increased biosafety and convenience in preclinical research. Exp Hematol 2006; 34 (5): 588-92.
51. + cells derived from human and non human primates. Blood 2002; 100: 823-32.
52. Jang JE, Shaw K, Yu XJ, et al. Specific and stable gene transfer to human embryonic stem cells using pseudotyped lentiviral vectors. Stem Cells Dev 2006; 15(1): 109-17.
53. Di Nunzio F, Piovani B, Cosset FL, Mavilio F, Stornaiuolo A. Transduction of human hematopoietic stem cells by lentiviral vectors pseudotyped with the RD114-TR chimeric envelope glycoprotein. Hum Gene Ther 2007; 18(9): 811-20.
54. Cronin J, Zhang X-Y, Reiser J. Altering the tropism of lentiviral vectors through pseudotyping. Curr Gene Ther 2005; 5(4): 387-98.
55. Zufferey R, Nagy D, Mandel RJ, Naldini L, Trono D. Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat Biotechnol 1997; 15: 871-75.
56. Dull T, Zufferey R, Kelly M, et al. A third-generation lentivirus vector with a conditional packaging system. J Virol 1998; 72: 8463-71.
57. Kim VN, Mitrophanous K, Kingsman SM, Kingsman AJ. Minimal requirement for a lentivirus vector based on human immunodeficiency virus type 1. J Virol 1998; 72: 811-6.
58. Wagner R, Graf M, Bieler K, et al. Rev-independent expression of synthetic gag-pol genes of human immunodeficiency virus type 1 and simian immunodeficiency virus: implications for the safety of lentiviral vectors. Hum Gene Ther 2000; 11(17): 2403-13.
59. Molina RP, Ye HQ, Brady J, et al. A synthetic Rev-independent bovine immunodeficiency virus-based packaging construct. Hum Gene Ther 2004; 15(9): 865-77.
60. Wu X, Wakefield JK, Liu H, et al. Development of a novel translentiviral vector that affords predictable safety. Mol Ther 2000; 2(1): 47-55.
61. Westerman KA, Ao Z, Cohen EA, Leboulch P. Design of a trans protease lentiviral packaging system that produces high titer virus. Retrovirology 2007; 4: 96-109.
62. Kappes JC, Wu X. Safety considerations in vector development. Somat Cell Mol Genet 2001; 126 (1/6): 147-58.
63. White SM, Renda M, Nam NY, et al. Lentivirus vectors using human and simian immunodeficiency virus elements. J Virol 1999; 73(4): 2832-40.
64. Kaye JF, Lever AM. Nonreciprocal packaging of human immunodeficiency virus type 1 and type 2 RNA: a possible role for the p2 domain of Gag in RNA encapsidation. J Virol 1998; 72(7): 5877-85.
65. Sachdeva G, D'Costa J, Cho JE, Kachapati K, Choudhry V, Arya SK. Chimeric HIV-1 and HIV-2 lentiviral vectors with added safety insurance. J Med Virol 2007; 79(2): 118-26.
66. Zufferey R, Dull T, Mandel RJ, et al. Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J Virol 1998; 72(12): 9873-80.
67. Bukovsky AA, Song JP, Naldini L. Interaction of human immunodeficiency virus-derived vectors with wild-type virus in transduced cells. J Virol 1999; 73(8): 7087-92.
68. Modlich U, Bohne J, Schmidt M, et al. Cell-culture assays reveal the importance of retroviral vector design for insertional genotoxicity. Blood 2006; 08(8): 2545-53.
69. Montini E, Cesana D, Schmidt M, et al. Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. Nat Biotechnol 2006; 24(6): 687-96.
70. Zychlinski D, Schambach A, Modlich U, et al. Physiological promoters reduce the genotoxic risk of integrating gene vectors. Mol Ther 2008; 16(4): 718-25.
71. Grunwald T, Pedersen FS, Wagner R, Uberla K. Reducing mobilization of simian immunodeficiency virus based vectors by primer complementation. J Gene Med 2004; 6: 147-54.
72. Logan, Haas ACDL, Kafri T, Kohn DB. Integrated self-inactivating lentiviral vectors produce full-length genomic transcripts competent for encapsidation and integration. J Virol 2004; 78: 8421-36.
73. Hanawa H, Persons DA, Nienhuis AW. Mobilization and mechanism of transcription of integrated self-inactivating lentiviral vectors. J Virol 2005; 79: 8410-21.
74. Sirven A, Pflumio F, Zennou V, et al. The human immunodeficiency virus type-1 central DNA flap is a crucial determinant for lentiviral vector nuclear import and gene transduction of human hematopoietic stem cells. Blood 2000; 96(13): 4103-10.
75. 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: 4685-94.
76. Zufferey R, Donello JE, Trono D, Hope TJ. Woodchuck hepatitis virus posttranscriptional regulatory element enhances expression of transgenes delivered by retroviral vectors. J Virol 1999; 73: 2886-92.
77. Schambach A, Bohne J, Baum C, et al. Woodchuck hepatitis virus post-transcriptional regulatory element deleted from X protein and promoter sequences enhances retroviral vector titer and expression. Gene Ther 2006; 13(7): 641-5.
78. Higashimoto T, Urbinati F, Perumbeti A, et al. The woodchuck hepatitis virus post-transcriptional regulatory element reduces readthrough transcription from retroviral vectors. Gene Ther 2007; 14(17): 1298-304.
79. Schambach A, Galla M, Maetzig T, Loew R, Baum C. Improving transcriptional termination of self-inactivating gamma-retroviral and lentiviral vectors. Mol Ther 2007; 15(6): 1167-73.
80. Zaiss AK, Son S, Chang LJ. RNA 3' readthrough of oncoretrovirus and lentivirus: implications for vector safety and efficacy. J Virol 2002; 76(14): 7209-19.
81. Yang Q, Lucas A, Son S, Chang LJ. Overlapping enhancer/promoter and transcriptional termination signals in the lentiviral long terminal repeat. Retrovirology 2007; 4: 4.
82. Sastry L, Xu Y, Johnson T, et al. Certification assays for HIV-1-based vectors: frequent passage of gag sequences without evidence of replication-competent viruses. Mol Ther 2003; 8: 830-9.
83. Escarpe P, Zayek N, Chin P, et al. Development of a sensitive assay for detection of replication-competent recombinant lentivirus in large-scale HIV-based vector preparations. Mol Ther 2003; 8(2): 332-41.
84. Maruggi G, Porcellini S, Facchini G, et al. Transcriptional enhancers induce insertional gene deregulation independently from the vector type and design. Mol Ther 2009; 17(5):851-6.
85. Apolonia L, Waddington SN, Fernandes C, et al. Stable gene transfer to muscle using non-integrating lentiviral vectors. Mol Ther 2007; 15(11): 1947-54.
86. Nightingale SJ, Hollis RP, Pepper KA, et al. Transient gene expression by nonintegrating lentiviral vectors. Mol Ther 2006; 13(6): 1121-32.
87. Yanez-Munoz RJ, Balaggan KS, MacNeil A, et al. Effective gene therapy with nonintegrating lentiviral vectors. Nat Med 2006; 12(3): 348-53.
88. Vargas J, Gusella GL, Najfeld V, Klotman ME, Cara A. Novel integrase-defective lentiviral episomal vectors for gene transfer. Hum Gene Ther 2004; 15(4): 361-72.
89. Cornu TI, Cathomen T. Targeted genome modifications using integrase-deficient lentiviral vectors. Mol Ther 2007; 15(12): 2107-13.
90. Lombardo A, Genovese P, Beausejour CM, et al. Gene editing in human stem cells using zinc finger nucleases and integrasedefective lentiviral vector delivery. Nat Biotechnol 2007; 25(11): 1298-306.
91. Moldt B, Staunstrup N, Jacobsen M, Yanez-Munoz RJ, Mikkelsen JG. Genomic insertion of lentiviral DNA circles directed by the yeast Fl recombinase. BMC Biotechnol 2008; 8: 60.
92. Sarkis C,Philippe S, Mallet J,Serguera C. Non-integrating lentiviral vectors. Curr Gene Ther 2008; 8(6): 430-7.
93. Staunstrup NH, Moldt B, Mátés L, et al. Hybrid lentivirustransposon vectors with a random integration profile in Human Cells. Mol Ther 2009; 17(7): 1205-14.
94. Van den Broeke A, Burny A. Retroviral vector biosafety: lessons from sheep. J Biomed Biotechnol 2003; 1(2003): 9-12.
95. Naldini L, Blömer U, Gallay P, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 1996; 272(5259): 263-7.
96. Milman G. HIV research in the SCID mouse: biosafety considerations. Science 1990; 250(4984): 1152.
97. Bauer G, Dao MA, Case SS, et al. In vivo biosafety model to assess the risk of adverse events from retroviral and lentiviral vectors. Mol Ther 2008; 16(7): 1308-15.
98. Rasmussen HB. Interactions between exogenous and endogenous retroviruses. J Biomed Sci 1997; 4(1):1-8.
99. Martinez I, Dornburg R. Partial reconstitution of a replication-competent retrovirus in helper cells with partial overlaps between vector and helper cell genomes. Hum Gene Ther 1996; 7(6): 705-12.
100. Siapati EK, Biger BW, Kashofer K, Themis M, Trasher AJ, Bonnet D. Murine leukemia following irradiation conditioning for transplantation of lentiviraly-modified hematopoietic stem cells. Eur J Heamatol 2007; 78(4), 303-13.
101. Mikkelsen JG, Pedersen FS. Genetic reassortment and patch repair by recombination in retroviruses. J Biomed Sci 2000; 7(2): 77-99.
102. Stoye JP. Endogenous retroviruses: still active after all these years? Curr Biol 2001; 11(22): R914-R916.
103. Patience C, Takeuchi Y, Cosset FL, Weiss RA. Packaging of endogenous retroviral sequences in retroviral vectors produced by murine and human packaging cells. J Virol 1998; 72(4): 2671-6.
104. Zeilfelder U, Frank O, Sparacio S, et al. The potential of retroviral vectors to cotransfer human endogenous retroviruses (HERVs) from human packaging cell lines. Gene 2007; 390 (1-2): 175-9.
105. Yang J, Bogerd HP, Peng S, et al. An ancient family of human endogenous retroviruses encodes a functional homolog of the HIV-1 Rev protein. Proc Natl Acad Sci USA 1999; 96: 13404-8.
106. Contreras-Galindo R, Gonzalez M, Almodovar-Camacho S, Gonzalez-Ramirez S, Lorenzo E, Yamamura Y. A new Real-Time-RT-PCR for quantitation of human endogenous retroviruses type K (HERV-K) RNA load in plasma samples: increased HERV-K RNA titers in HIV-1 patients with HAART non-suppressive regimens. J Virol Methods 2006; 136: 51-7.
107. Contreras-Galindo R, Kaplan MH, Markovitz DM, Lorenzo E, Yamamura Y. Detection of HERV-K(HML-2) viral RNA in plasma of HIV type 1-infected individuals. AIDS Res Hum Retro-viruses 2006; 22: 979-84.
108. Garrison KE, Jones RB, Meiklejohn DA, et al. T cell responses to human endogenous retroviruses in HIV-1 infection. PLoS Pathog 2007; 3(11): e165.
109. Dewannieux M, Harper F, Richaud A, et al. Identification of an infectious progenitor for the multiple-copy HERV-K human endogenous retroelements. Genome Res 2006; 16(12): 1548-56.
110. Lee YN, Bieniasz PD. Reconstitution of an infectious human endogenous retrovirus. PLoS Pathog 2007; 3(1): e10. J Gene Med Clin Trial. Available at: http://www.wiley.co.uk/ genmed/clinical/ [Accessed 9 June 2009].
111. ACGM (2000). Compendium of Guidance from UK Health and Safety Commission's Advisory Committee on Genetic Modification. Health & Safety Executive, London. Available at: http://www.hse.gov.uk/biosafety/gmo/acgm/ acgmcomp/ [Accessed 9 June 2009].
112. Zentrale Kommission für die Biologische Sicherheit (D). Available at: http://www.bvl.bund.de/cln-027/nn-491798/DE/06--Gentechnik/093--ZKBS/zkbs-- node.html--nnn=true [Accessed 9 June 2009].
113. Commission de Génie Génétique (FR), 2007: Notice IV : Principes de classement des opérations mettant en oeuvre des vecteurs dérivés de lentivirus. Available at : http://wwww. enseignementsuprecherche. gouv.fr/commis/genetique/notice4.pdf. [Accessed 9 June 2009].
114. Commissie Genetische Modificatie (NL), 2005, CGM/051215-01: advies handelingen met lentivirale vectoren getransduceerde zoogdiercellen (in Dutch)
115. Available at : http://www.cogem.net/main-adviesdetail-home.aspx? pageid=13&loc=2&version=&mode=&id=297. [Accessed 9 June 2009].
116. Commissie Genetische Modificatie (NL), 2005, CGM/050309-01 (in Dutch) Available at: http://www.cogem.net/main-adviesdetailhome. aspx? pageid=13&loc=2&version=&mode=&id=255 [Accessed 9 June 2009].
117. Commissie Genetische Modificatie (NL), 2006, CGM/060710-01 : Advies handelingen met lentiviraal getransduceerde cellen in apen (IG 05-020/03) (in Dutch) Available at: http://www.cogem.net/main-adviesdetail-home.aspx?pageid= 13&loc=2&version=& mode=&id= 332. [Accessed 9 June 2009].
118. Commissie Genetische Modificatie (NL), 2006, CGM/061003: Advies handelingen met lentivirale vectoren in konijnen (in Dutch) Available at: http://www.cogem.net/main-adviesdetail-home.aspx? pageid=13&loc= 2&version=&mode=&id=350. [Accessed 9 June 2009].
119. NIH (2006) Recombinant DNA advisory Committee (RAC) Guidance document. Biosafety Considerations for research with lentiviral vectors. Available at: www4.od.nih.gov/oba/RAC/Guidance/ LentiVirus- Containment/index.htm. [Accessed 9 June 2009].
120. Debyser Z. Biosafety of lentiviral vectors. Curr Gene Ther 2003; 3: 517-25.
121. Pauwels K, Herman P, Van Vaerenbergh B, et al. Animal cell cultures: Risk Assessment and biosafety recommendations. Appl Biosaf J 2007; 12(1): 26-38.
122. Tang SB, Levy JA. Inactivation of HIV-1 by trypsin and its use in demonstrating specific virus infection of cells. J Virol Methods 1991; 33: 39-46.
123. Shokralla S, He Y, Wanas, E, Ghosh HP. Mutations in a carboxyterminal region of vesicular stomatitis virus glycoprotein G that affect membrane fusion activity. Virology 1998; 242: 39-50.
124. Higashikawa F, Chang L. Kinetic analyses of stability of simple and complex retroviral vectors. Virology 2001; 280: 124-31.
125. Wilflingseder D, Banki Z, Dierich MP, Stoiber H. Mechanisms promoting dendritic cell-mediated transmission of HIV. Mol Immunol 2005; 42: 229-37.
126. Wu Z, Chen Z, Phillips, DM. Human genital epithelial cells capture cell-free human immunodeficiency virus type 1 and transmit the virus to CD4+ cells: implications for mechanisms of sexual transmission. J Infect Dis 2003; 188: 1473-82.
127. Kwon DS, Gregorio G, Bitton N, Hendrickson WA, Littman DR. DC-SIGN-mediated internalization of HIV is required for transenhancement of T cell infection. Immunity 2002; 16: 135-44.
128. Karlen S, Zufferey R. Declassification of rodents exposed to third generation HIV-derived vectors into class 1 animals. Appl Biosaf 2007; 12(2): 93-99.
129. European Medicines Agency. Guideline on development and manufacture of lentiviral vectors. 2005. CHMP/BWP/2458/03. Available at: http//: www.emea.europa.eu/pdfs/human/bwp/245803en.pdf
130. Wilson SJ, Webb BL, Ylinen LM, Verschoor E, Heeney J, Towers GJ. Independent evolution of an antiviral TRIMCyp in rhesus macaques. Proc Natl Acad Sci USA 2008; 105(9): 3557-62.
131. Bergmans H, Logie C, Van Maanen K, Hermsen H, Meredyth M, Van Der Vlugt C. Identification of potentially hazardous human gene products in GMO risk assessment. Environ Biosaf Res 2008; 7(1): 1-9.
132. Stewart HJ, Leroux-Carlucci MA, Sion CJ, Mitrophanous KA, Radcliffe PA. Development of inducible EIAV-based lentiviral vector packaging and producer cell lines. Gene Ther 2009; 16(6): 805-14.