Historically, retroviral vectors have been the most frequently used type of gene delivery vectors for clinical gene therapy. In particular, vectors based on murine leukemia virus (MLV) and related retroviruses have been employed in almost half of the current gene therapy clinical protocols (http://www.wiley.co.uk/genetherapy). The major advantages of retroviral vectors are (1) ease of manipulation for insertion of the therapeutic gene; (2) ability to stably integrate into the target cell genome; (3) relatively high titer of the recombinant retroviruses; (4) a wide range of target species and cells that can be infected without any apparent adverse pathology; and (5) relatively simple procedure for preparation of the recombinant virus. However, the current retroviral vector have potential disadvantages as well, such as (1) requirement for cell division for integration, limiting their in vivo applications; and (2) random integration into host chromosome, resulting in possible insertional mutagenesis or oncogene activation. However, recent developments in virus packaging systems, use of modified or different envelope proteins for packaging, and modifications with the cis-acting regulatory elements to regulate transgene expression have allowed for the safe and efficient clinical application of retroviral vectors. This chapter provides a background on retrovirus-based vector systems as well as provides an update regarding improvements in retroviral vector for gene transfer.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Adam, M.A., and Miller, A.D. 1988, Identification of a signal in a murine retrovirus that is sufficient for packaging of nonretroviral RNA into virions. J Virol. 62: 3802.
Bahrami, S., Duch, M., and Pedersen, F.S. 2004, Change of tropism of SL3-2 murine leukemia virus, using random mutational libraries. J Virol. 78: 9343.
Bender, M.A., Palmer, T.D., Gelinas, R.E., and Miller, A.D. 1987, Evidence that the packaging signal of Moloney murine leukemia virus extends into the gag region. J Virol. 61: 1639.
Bupp, K., and Roth, M.J. 2003, Targeting a retroviral vector in the absence of a known cell-targeting ligand. Hum Gene Ther. 14: 1557.
Burns, D.P., Collignon, C., and Desrosiers, R.C. 1993, Simian immunodeficiency virus mutants resistant to serum neutralization arise during persistent infection of rhesus monkeys. J Virol. 67: 4104.
Cepko, C.L., Roberts, B.E., and Mulligan, R.C. 1984, Construction and applications of a highly transmissible murine retrovirus shuttle vector. Cell. 37: 1053.
Chadwick, M.P., Morling, F.J., Cosset, F.L., and Russell, S.J. 1999, Modification of retroviral tropism by display of IGF-I. J Mol Biol. 285: 485.
Challita, P.M., Skelton, D., el-Khoueiry, A., Yu, X.J., Weinberg, K., and Kohn, D.B. 1995, Multiple modifications in cis elements of the long terminal repeat of retroviral vectors lead to increased expression and decreased DNA methylation in embryonic carcinoma cells. J Virol. 69: 748.
Choulika, A., Guyot, V., and Nicolas, J.F. 1996, Transfer of single gene-containing long terminal repeats into the genome of mammalian cells by a retroviral vector carrying the cre gene and the loxP site. J Virol. 70: 1792.
Chu, T.H., and Dornburg, R. 1995, Retroviral vector particles displaying the antigen-binding site of an antibody enable cell-type-specific gene transfer. J Virol. 69: 2659.
Ciafre, S.A., Barillari, G., Bongiorno-Borbone, L., Wannenes, F., Izquierdo, M., and Farace, M.G. 2002, A tricistronic retroviral vector expressing natural antiangiogenic factors inhibits angiogenesis in vitro, but is not able to block tumor progression in vivo. Gene Ther. 9: 297.
Cone, R.D., Weber-Benarous, A., Baorto, D., and Mulligan, R.C. 1987, Regulated expression of a complete human beta-globin gene encoded by a transmissible retrovirus vector. Mol Cell Biol. 7: 887.
Crittenden, M., Gough, M., Chester, J., Kottke, T., Thompson, J., Ruchatz, A., Clackson, T., Cosset, F.L., Chong, H., Diaz, R.M., Harrington, K., Alvarez Vallina, L., and Vile, R. 2003, Pharmacologically regulated production of targeted retrovirus from T cells for systemic antitumor gene therapy. Cancer Res. 63: 3173.
Danos, O. and Mulligan, R.C. 1988, Safe and efficient generation of recombinant retroviruses with amphotropic and ecotropic host ranges. Proc Natl Acad Sci U S A. 85: 6460.
Davies, M.V. and Kaufman, R.J. 1992, The sequence context of the initiation codon in the encephalomyocarditis virus leader modulates efficiency of internal translation initiation. J Virol. 66: 1924.
De Felipe, P. 2004, Skipping the co-expression problem: the new 2A “CHYSEL” technology. Genet Vaccines Ther. 2: 13
De Felipe, P., and Izquierdo, M. 2000, Tricistronic and tetracistronic retroviral vectors for gene transfer. Hum Gene Ther. 11: 1921.
Donahue, R.E., Kessler, S.W., Bodine, D., McDonagh, K., Dunbar, C., Goodman, S., Agricola, B., Byrne, E., Raffeld, M., Moen, R., et al. 1992, Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer. J Exp Med. 176: 1125.
Dougherty, J.P., Wisniewski, R., Yang, S.L., Rhode, B.W., Temin, H.M. 1989, New retrovirus helper cells with almost no nucleotide sequence homology to retrovirus vectors. J Virol. 63: 3209.
Douin, V., Bornes, S., Creancier, L., Rochaix, P., Favre, G., Prats, A.C., and Couderc, B. 2004, Use and comparison of different internal ribosomal entry sites (IRES) in tricistronic retroviral vectors. BMC Biotechnol. 4: 16.
Fassati, A., Bardoni, A., Sironi, M., Wells, D.J., Bresolin, N., Scarlato, G., Hatanaka, M., Yamaoka, S., and Dickson, G. 1998, Insertion of two independent enhancers in the long terminal repeat of a self-inactivating vector results in high-titer retroviral vectors with tissue-specific expression. Hum Gene Ther. 9: 2459.
Fernex, C., Dubreuil, P., Mannoni, P., and Bagnis, C. 1997, Cre/loxP-mediated excision of a neomycin resistance expression unit from an integrated retroviral vector increases long terminal repeat-driven transcription in human hematopoietic cells. J Virol. 71: 7533.
Ferrari, G., Salvatori, G., Rossi, C., Cossu, G., and Mavilio, F. 1995, A retroviral vector containing a muscle-specific enhancer drives gene expression only in differentiated muscle fibers. Hum Gene Ther. 6: 733.
Finer, M.H., Dull, T.J., Qin, L., Farson, D., and Roberts, M.R. 1994, Kat: A high-efficiency retroviral transduction system for primary human T lymphocytes. Blood. 83: 43.
Furth, P.A., St Onge, L., Boger, H., Gruss, P., Gossen, M., Kistner, A., Bujard, H., and Hennighausen, L. 1994, Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. Proc Natl Acad Sci U S A. 91: 9302.
Fussenegger, M., Mazur, X., and Bailey, J.E. 1998, TRIDENT, a novel vector family for tricistronic gene expression in mammalian cells. Biotechnol Bioeng. 57: 1.
Gossen, M., and Bujard, H. 1992, Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci U S A. 89: 5547.
Grande, A., Piovani, B., Aiuti, A., Ottolenghi, S., Mavilio, F., and Ferrari, G. 1999, Transcriptional targeting of retroviral vectors to the erythroblastic progeny of transduced hematopoietic stem cells. Blood. 93: 3276.
Grez, M., Akgun, E., Hilberg, F., and Ostertag, W. 1990, Embryonic stem cell virus, a recombinant murine retrovirus with expression in embryonic stem cells. Proc Natl Acad Sci U S A. 87: 9202.
Guild, B.C., Finer, M.H., Housman, D.E., and Mulligan, R.C. 1988, Development of retrovirus vectors useful for expressing genes in cultured murine embryonal cells and hematopoietic cells in vivo. J Virol. 62: 3795.
Han, X., Kasahara, N., and Kan, Y.W. 1995, Ligand-directed retroviral targeting of human breast cancer cells. Proc Natl Acad Sci U S A. 92: 9747.
Hawley, R.G., Lieu, F.H., Fong, A.Z., and Hawley, T.S. 1994, Versatile retroviral vectors for potential use in gene therapy. Gene Ther. 1: 136.
Hildinger, M., Abel, K.L., Ostertag, W., and Baum, C. 1999, Design of 5’ untranslated sequences in retroviral vectors developed for medical use. J Virol. 73: 4083.
Hoess, R.H. and Abremski, K. 1984, Interaction of the bacteriophage P1 recombinase Cre with the recombining site loxP. Proc Natl Acad Sci U S A. 81: 1026.
Indraccolo, S., Minuzzo, S., Habeler, W., Zamarchi, R., Fregonese, A., Gunzburg, W.H., Salmons, B., Uckert, W., Chieco-Bianchi, L., and Amadori, A. 2000, Modulation of Moloney leukemia virus long terminal repeat transcriptional activity by the murine CD4 silencer in retroviral vectors. Virology. 276: 83.
Jiang, A., Chu, T.H., Nocken, F., Cichutek, K., and Dornburg, R. 1998, Cell-type-specific gene transfer into human cells with retroviral vectors that display single-chain antibodies. J Virol. 72: 10148.
Joyner, A.L. and Bernstein, A. 1983, Retrovirus transduction: generation of infectious retroviruses expressing dominant and selectable genes is associated with in vivo recombination and deletion events. Mol Cell Biol. 3: 2180.
Kasahara, N., Dozy, A.M., and Kan, Y.W. 1994, Tissue-specific targeting of retroviral vectors through ligand-receptor interactions. Science. 266: 1373.
Kim, S.H., Yu, S.S., Park, J.S., Robbins, P.D., An, C.S., and Kim, S. 1998, Construction of retroviral vectors with improved safety, gene expression, and versatility. J Virol. 72: 994.
Konishi, H., Ochiya, T., Chester, K.A., Begent, R.H., Muto, T., Sugimura, T., Terada, M., and Begent, R.H. 1998, Targeting strategy for gene delivery to carcinoembryonic antigen-producing cancer cells by retrovirus displaying a single-chain variable fragment antibody. Hum Gene Ther. 9: 235.
Kraunus, J., Schaumann, D.H., Meyer, J., Modlich, U., Fehse, B., Brandenburg, G., von Laer, D., Klump, H., Schambach, A., Bohne, J., and Baum, C. 2000, Self-inactivating retroviral vectors with improved RNA processing. Gene Ther. 11: 1568.
Leboulch, P., Huang, G.M., Humphries, R.K., Oh, Y.H., Eaves, C.J., Tuan, D.Y., and London, I.M. 1994, Mutagenesis of retroviral vectors transducing human beta-globin gene and beta-globin locus control region derivatives results in stable transmission of an active transcriptional structure. EMBO J. 13: 3065.
Li, M., Hantzopoulos, P.A., Banerjee, D., Zhao, S.C., Schweitzer, B.I., Gilboa, E., and Bertino, J.R. 1992, Comparison of the expression of a mutant dihydrofolate reductase under control of different internal promoters in retroviral vectors. Hum Gene Ther. 3: 381.
Lim, B., Williams, D.A., and Orkin, S.H. 1987, Retrovirus-mediated gene transfer of human adenosine deaminase: Expression of functional enzyme in murine hematopoietic stem cells in vivo. Mol Cell Biol. 7: 3459.
Loew, R., Selevsek, N., Fehse, B., von Laer, D., Baum, C., Fauser, A., and Kuehlcke, K. 2004, Simplified generation of high-titer retrovirus producer cells for clinically relevant retroviral vectors by reversible inclusion of a lox-P-flanked marker gene. Mol Ther. 9: 738.
Mann, R., Mulligan, R.C., and Baltimore, D. 1983, Construction of a retrovirus packaging mutant and its use to produce helper-free defective retrovirus. Cell. 33: 153.
McClure, M.O., Sommerfelt, M.A., Marsh, M., and Weiss, R.A. 1990, The pH independence of mammalian retrovirus infection. J Gen Virol. 71: 767-73.
McIvor, R.S. 1990, Deletion in a recombinant retroviral vector resulting from a cryptic splice donor signal in the Moloney leukemia virus envelope gene. Virology. 176: 652.
Miller, A.D. and Rosman, G.J. 1989, Improved retroviral vectors for gene transfer and expression. Biotechniques. 7: 980.
Miller, A.D., Garcia, J.V., von Suhr, N., Lynch, C.M., Wilson, C., and Eiden, M.V. 1991, Construction and properties of retrovirus packaging cells based on gibbon ape leukemia virus. J Virol. 65: 2220.
Mizuguchi, H., Xu, Z., Ishii-Watabe, A., Uchida, E., and Hayakawa, T. 2000, IRES-dependent second gene expression is significantly lower than cap-dependent first gene expression in a bicistronic vector. Mol Ther. 1: 376.
Morgan, R.A., Couture, L., Elroy-Stein, O., Ragheb, J., Moss, B., and Anderson, W.F. 1992, Retroviral vectors containing putative internal ribosome entry sites: Development of a polycistronic gene transfer system and applications to human gene therapy. Nucleic Acids Res. 20: 1293.
Ohashi, T., Boggs, S., Robbins, P.D., Bahnson, A., Patrene, K., Wei, F.S., Wei, J.F., Li, J., Lucht, L., Fei, Y., et al. 1992, Efficient transfer and sustained high expression of the human glucocerebrosidase gene in mice and their functional macrophages following transplantation of bone marrow transduced by a retroviral vector. Proc Natl Acad Sci U S A. 89: 11332.
Pear, W.S., Nolan, G.P., Scott, M.L., and Baltimore, D. 1993, Production of high-titer helper-free retroviruses by transient transfection. Proc Natl Acad Sci U S A. 90: 8392.
Pollock, R., Issner, R., Zoller, K., Natesan, S., Rivera, V.M., and Clackson, T. 2000, Delivery of a stringent dimerizer-regulated gene expression system in a single retroviral vector. Proc Natl Acad Sci U S A. 97: 13221.
Richardson, T.B., Kaspers, J., and Porter, C.D. 2004, Retroviral hybrid LTR vector strategy: functional analysis of LTR elements and generation of endothelial cell specificity. Gene Ther. 11: 775.
Rivera, V.M., Clackson, T., Natesan, S., Pollock, R., Amara, J.F., Keenan, T., Magari, S.R, Phillips, T., Courage, N.L., Cerasoli, F., Jr Holt, D.A., and Gilman, M. 1996, A humanized system for pharmacologic control of gene expression. Nat Med. 2: 1028.
Russ, A.P., Friedel, C., Grez, M., and von Melchner, H. 1996, Self-deleting retrovirus vectors for gene therapy. J Virol. 70: 4927.
Sadelain, M., Wang, C.H., Antoniou, M., Grosveld, F., and Mulligan, R.C. 1995, Generation of a high-titer retroviral vector capable of expressing high levels of the human beta-globin gene. Proc Natl Acad Sci U S A. 92: 6728.
Schambach, A., Wodrich, H., Hildinger, M., Bohne, J., Krausslich, H.G., and Baum, C. 2000, Context dependence of different modules for posttranscriptional enhancement of gene expression from retroviral vectors. Mol Ther. 2: 435.
Shimotohno, K. and Temin, H.M. 1981, Formation of infectious progeny virus after insertion of herpes simplex thymidine kinase gene into DNA of an avian retrovirus. Cell. 2: 67.
Sirin, O. and Park, F. 2003, Regulating gene expression using self-inactivating lentiviral vectors containing the mifepristone-inducible system. Gene. 323: 67.
Somia, N.V., Zoppe, M., and Verma, I.M. 1995, Generation of targeted retroviral vectors by using single-chain variable fragment: An approach to in vivo gene delivery. Proc Natl Acad Sci U S A. 92: 7570.
Soneoka, Y., Cannon, P.M., Ramsdale, E.E., Griffiths, J.C., Romano, G., Kingsman, S.M., and Kingsman, A.J. 1995. A transient three-plasmid expression system for the production of high titer retroviral vectors. Nucleic Acids Res. 23: 628.
Szymczak, A.L., Workman, C.J., Wang, Y., Vignali, K.M., Dilioglou, S., Vanin, E.F., and Vignali, D.A. 2004, Correction of multi-gene deficiency in vivo using a single ‘self-cleaving’ 2A peptide-based retroviral vector. Nat Biotechnol. 22: 589.
Tabin, C.J., Hoffmann, J.W., Goff, S.P., and Weinberg, R.A. 1982, Adaptation of a retrovirus as a eucaryotic vector transmitting the herpes simplex virus thymidine kinase gene. Mol Cell Biol. 2: 426.
Trubetskoy, A.M., Okenquist, S.A., and Lenz, J. 1999, R region sequences in the long terminal repeat of a murine retrovirus specifically increase expression of unspliced RNAs. J Virol. 73: 3477.
Wei, C.M., Gibson, M., Spear, P.G., and Scolnick, E.M. 1981, Construction and isolation of a transmissible retrovirus containing the src gene of Harvey murine sarcoma virus and the thymidine kinase gene of herpes simplex virus type 1. J Virol. 39: 935.
Yee, J.K., Friedmann, T., and Burns, J.C. 1994, Generation of high-titer pseudotyped retroviral vectors with very broad host range. Methods Cell Biol. 43 Pt A: 99.
Yu, S.F., von Ruden, T., Kantoff, P.W., Garber, C., Seiberg, M., Ruther, U., Anderson, W.F., Wagner, E.F., and Gilboa, E. 1986, Self-inactivating retroviral vectors designed for transfer of whole genes into mammalian cells. Proc Natl Acad Sci U S A. 83: 3194.
Yu, S.S., Kim, J.M., and Kim, S. 2000, High efficiency retroviral vectors that contain no viral coding sequences. Gene Ther. 7: 797.
Zufferey, R., Donello, J.E., Trono, D., and Hope, T.J. 1999, Woodchuck hepatitis virus posttranscriptional regulatory element enhances expression of transgenes delivered by retroviral vectors. J Virol. 73: 2886.
Author information
Authors and Affiliations
Rights and permissions
Copyright information
© 2007 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Kim, SH., Robbins, P.D. (2007). Retroviral Vectors for Gene Therapy. In: Lysosomal Storage Disorders. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-70909-3_5
Download citation
DOI: https://doi.org/10.1007/978-0-387-70909-3_5
Publisher Name: Springer, Boston, MA
Print ISBN: 978-0-387-70908-6
Online ISBN: 978-0-387-70909-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)