Advertisement

Journal of Biomedical Science

, Volume 3, Issue 6, pp 365–378 | Cite as

Transcriptional silencing of retroviral vectors

  • Anders H. Lund
  • Mogens Duch
  • Finn Skou Pedersen
Review

Abstract

Although retroviral vector systems have been found to efficiently transduce a variety of cell types in vitro, the use of vectors based on murine leukemia virus in preclinical models of somatic gene therapy has led to the identification of transcriptional silencing in vivo as an important problem. Extinction of long-term vector expression has been observed after implantation of transduced hematopoietic cells as well as fibroblasts, myoblasts and hepatocytes. Here we review the influence of vector structure, integration site and cell type on transcriptional silencing. While down-regulation of proviral transcription is known from a number of cellular and animal models, major insight has been gained from studies in the germ line and embryonal cells of the mouse. Key elements for the transfer and expression of retroviral vectors, such as the viral transcriptional enhancer and the binding site for the tRNA primer for reverse transcription may have a major influence on transcriptional silencing. Alterations of these elements of the vector backbone as well as the use of internal promoter elements from housekeeping genes may contribute to reduce transcriptional silencing. The use of cell culture and animal models in the testing and improvement of vector design is discussed.

Key words

Retroviral vectors Gene therapy Stem cells Transcription Silence Inactivation Integration site Position effects Methylation Primer-binding site 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Akgün E, Ziegler M, Grez M. Determinants of retrovirus gene expression in embryonal carcinoma cells. J Virol 65:382–388;1991.PubMedGoogle Scholar
  2. 2.
    Antequera F, Boyes J, Bird A. High levels of de novo methylation and altered chromatin structure at CpG islands in cell lines. Cell 62:503–514;1990.CrossRefPubMedGoogle Scholar
  3. 3.
    Antequera F, Macleod D, Bird AP. Specific protection of methylated CpGs in mammalian nuclei. Cell 58:509–517;1989.CrossRefPubMedGoogle Scholar
  4. 4.
    Apperley JF, Luskey BD, Williams DA. Retroviral gene transfer of human adenosine deaminase in murine hematopoietic cells: Effect of selectable marker sequences on long-term expression. Blood 78:310–317;1991.PubMedGoogle Scholar
  5. 5.
    Barklis E, Mulligan RC, Jaenisch R. Chromosomal position or virus mutation permits retrovirus expression in embryonal carcinoma cells. Cell 47:391–399;1986.CrossRefPubMedGoogle Scholar
  6. 6.
    Baum C, Hegewisch-Becker S, Eckert H-G, Stocking C, Ostertag W. Novel retroviral vectors for efficient expression of the multidrug resistance(mdr-1) gene in early hematopoetic cells. J Virol 69:7541–7547;1995.PubMedGoogle Scholar
  7. 7.
    Bender MA, Gelinas RE, Miller AD. A majority of mice show long-term expression of a human beta-globulin gene after retrovirus transfer into hematopoietic stem cells. Mol Cell Biol 9:1426–1434;1989.PubMedGoogle Scholar
  8. 8.
    Berwin B, Barklis E. Retrovirus-mediated insertion of expressed and non-expressed genes at identical chromosomal locations. Nucleic Acids Res 21:2399–2407;1993.PubMedGoogle Scholar
  9. 9.
    Bird A. The essentials of DNA methylation. Cell 70:5–8;1992.CrossRefPubMedGoogle Scholar
  10. 10.
    Bird AP. CpG-rich islands and the function of DNA methylation. Nature 321:209–213;1986.CrossRefPubMedGoogle Scholar
  11. 11.
    Bird AP. DNA methylation — How important in gene control? Nature 307:503–504;1984.Google Scholar
  12. 12.
    Bodine DM, Moritz TM, Donahue RE, Luskey BD, Kessler SW, Martin DIK, Orkin SH, Nienhuis AW, Williams DA. Long-term in vivo expression of a murine adenosine deaminase gene in rhesus monkey hematopoietic cells of multiple lineages after retroviral mediated gene transfer into CD34+ bone marrow cells. Blood 82:1975–1980;1993.PubMedGoogle Scholar
  13. 13.
    Boris Lawrie KA, Temin HM. Recent advances in retrovirus vector technology. Curr Opin Genet Dev 3:102–109;1993.CrossRefPubMedGoogle Scholar
  14. 14.
    Bowtell DDL, Cory S, Johnson GR, Gonda TJ. Comparison of expression in hematopoietic cells by retroviral vectors carrying two genes. J Virol 62:2464–2473;1988.PubMedGoogle Scholar
  15. 15.
    Challita PM, Skelton D, el Khoueiry A, Yu XJ, Weinberg K, Kohn DB. Multiple modifications in cis elements of the long terminal repeat of retroviral vectors lead to increased expressions and decreased DNA methylation in embryonic carcinoma cells. J Virol 69:748–755;1995.PubMedGoogle Scholar
  16. 16.
    Challita PM, Kohn DB. Lack of expression from a retroviral vector after transduction of murine hematopoietic stem cells is associated with methylation in vivo. Proc Natl Acad Sci USA 91:2567–2571;1994.PubMedGoogle Scholar
  17. 17.
    Colicelli J, Goff SP. Isolation of a recombinant murine leukemia virus utilizing a new primer tRNA. J Virol 57:37–45;1987.Google Scholar
  18. 18.
    Coffin JM. Retroviridae: The viruses and their replication. In: Fields BN, Knipe DM, Howley PM, Chanock RM, Melnick JL, Monath TP, Roizman B, Straus SE, eds. Virology. Philadelphia, Raven Publishers, 1767–1848;1996.Google Scholar
  19. 19.
    Correll PH, Colilla S, Karlsson S. Retroviral vector design for long-term expression in murine hematopietic cells in vivo. Blood 84:1812–1822;1994.PubMedGoogle Scholar
  20. 20.
    Correll PH, Colilla S, Dave HP, Karlsson S. High levels of human glucocerebrosidase activity in macrophages of long-term reconstituted mice after retroviral infection of hematopoietic stem cells. Blood 80:331–336;1992.PubMedGoogle Scholar
  21. 21.
    Crystal RG. Transfer of genes to humans: Early lessons and obstacles to success. Science 270:404–410;1995.PubMedGoogle Scholar
  22. 22.
    D'Auriol L, Yand WK, Tobaly J, Cavalieri F, Peries J, Emanoil-Ravicovitch R. Studies on the restriction of ecotropic murine leukemia virus replication in murine teratocarcinoma cells. J Gen Virol 55:117–122;1981.PubMedGoogle Scholar
  23. 23.
    Dai Y, Roman M, Naviaux RK, Verma IM. Gene therapy via primary myoblasts: Long-term expression of factor IX protein following transplantation in vivo. Proc Natl Acad Sci USA 89:10892–10895;1992.PubMedGoogle Scholar
  24. 24.
    Damjanov I, Bagasra O, Solter D. Genetic and epigenetic factors regulate the malignancy of embryo-derived teratomas. In: Teratoma Stem Cells. New York, CSH Conferences on Cell Proliferation, 10:501–517;1983.Google Scholar
  25. 25.
    Duch M, Paludan K, Lovmand J, Pedersen L, Jorgensen P, Pedersen FS. A correlation between dexamethasone inducibility and basal expression levels of retroviral vector proviruses. Nucleic Acids Res 21:4777–4782;1993.PubMedGoogle Scholar
  26. 26.
    Duch M, Paludan K, Lovmand J, Sorensen MS, Jorgensen P, Pedersen FS. The effect of selection for high-level vector expression on the genetic and functional stability of a single transcript vector derived from a low-leukemogenic murine retrovirus. Hum Gene Ther 6:289–296;1995.PubMedGoogle Scholar
  27. 27.
    Duch M, Paludan K, Jorgensen P, Pedersen FS. Lack of correlation between basal expression levels and suceptibility to transcriptional shutdown among single-gene murine leukemia virus vector proviruses. J Virol 68:5596–5601;1994.PubMedGoogle Scholar
  28. 28.
    Dzierzak EA, Papayannopoulou T, Mulligan RC. Lineage-specific expression of a human beta-globin gene in murine bone marrow transplant recipients reconstituted with retrovirus-transduced stem cells. Nature 331:35–41;1988.CrossRefPubMedGoogle Scholar
  29. 29.
    Emerman M, Temin HM. Comparison of promoter suppression in avian and murine retrovirus vectors. Nucleic Acids Res 14:9381–9396;1986.PubMedGoogle Scholar
  30. 30.
    Emerman M, Temin HM. Genes with promoters in retrovirus vectors can be independently suppressed by an epigenetic mechanism. Cell 39:449–467;1984.CrossRefPubMedGoogle Scholar
  31. 31.
    Feuer G, Taketo M, Hanecak RC, Fan H. Two blocks in Moloney murine leukemia virus expression in undifferentiated F9 embryonal carcinoma cells as determined by transient expression assays. J Virol 63:2317–2324;1989.PubMedGoogle Scholar
  32. 32.
    Fincham VJ, Wyke JA. Differences between cellular integration sites of transcribed and nontranscribed Rous sarcoma proviruses. J Virol 65:461–463;1991.PubMedGoogle Scholar
  33. 33.
    Franz T, Hilberg F, Seliger B, Stocking C, Ostertag W. Retroviral mutants efficiently expressed in embryonal carcinoma cells. Proc Natl Acad Sci USA 83:3292–3296;1986.PubMedGoogle Scholar
  34. 34.
    Ghattas IR, Sanes JR, Majors JE. The encephalomyocarditis virus internal ribosome entry site allows efficient coexpression of two genes from a recombinant provirus in cultured cells and in embryos. Mol Cell Biol 11:5848–5859;1991.PubMedGoogle Scholar
  35. 35.
    Gautsch JW, Wilson MC. Delayed de novo methylation in teratocarcinomas suggests additional tissue-specific mechanisms for controlling gene expression. Nature 301:32–37;1983.CrossRefPubMedGoogle Scholar
  36. 36.
    Gilboa E, Mitra SW, Goff S, Baltimore D. A detailed model of reverse transcription and tests of crucial aspects. Cell 18:93–100;1979.CrossRefPubMedGoogle Scholar
  37. 37.
    Gorman CM, Rigby PWJ, Lane DP. Negative regulation of viral enhancers in undifferentiated embryonal stem cells. Cell 42:519–526;1985.CrossRefPubMedGoogle Scholar
  38. 38.
    Grez M, Akgun E, Hilberg F, Ostertag W. Embryonic stem cell virus, a recombinant murine retrovirus with expression in embryonic stem cells. Proc Natl Acad Sci USA 87:9202–9206;1990.PubMedGoogle Scholar
  39. 39.
    Guild BC, Finer MH, Housman DE, Mulligan RC. Development of retrovirus vectors useful for expressing genes in cultured murine embryonal cells and hematopoietic cells in vivo. J Virol 62:3795–3801;1988.PubMedGoogle Scholar
  40. 40.
    Harbers K, Jähner D, Jaenisch R. Microinjection of cloned retroviral genomes into mouse zygotes: Integration and expression in the animal. Nature 293:540–542;1981.CrossRefPubMedGoogle Scholar
  41. 41.
    Harbers K, Schnieke A, Stuhlman H, Jähner D, Jaenish R. DNA methylation and gene-expression: Endogenous retroviral genome becomes infectious after molecular cloning. Proc Natl Acad Sci USA 78:7609–7613;1981.PubMedGoogle Scholar
  42. 42.
    Hilberg F, Stocking C, Ostertag W, Grez M. Functional analysis of a retroviral host-range mutant: Altered long terminal repeat sequences allow expression in embryonal carcinoma cells. Proc Natl Acad Sci USA 84:5232–5236;1987.PubMedGoogle Scholar
  43. 43.
    Hoeben RC, Migchielsen AA, van der Jagt RC, van Ormondt H, van der Erb AJ. Inactivation of the Moloney murine leukemia virus long terminal repeat in murine fibroblast cell lines is associated with methylation and dependent on its chromosomal position. J Virol 65:904–912;1991.PubMedGoogle Scholar
  44. 44.
    Jähner D, Jaenisch R. Chromosomal position and specific demethylation in enhancer sequences of germ line-transmitted retroviral genomes during mouse development. Mol Cell Biol 5:2212–2220;1985.PubMedGoogle Scholar
  45. 45.
    Jähner D, Stuhlmann H, Stewart CL, Harbers K, Lohler J, Simon I, Jaenisch R. De novo methylation and expression of retroviral genomes during mouse embryogenesis. Nature 298:623–628;1982.CrossRefPubMedGoogle Scholar
  46. 46.
    Jang SK, Krausslich HG, Nicklin MJ, Duke GM, Palmenberg AC, Wimmer E. A segment of the 5' nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation. J Virol 62:2636–2643;1988.PubMedGoogle Scholar
  47. 47.
    Kaleko M, Garcia JV, Osborne WRA, Miller AD. Expression of human adenosine deaminase in mice after transplantation of genetically-modified bone marrow. Blood 75:1733–1741;1990.PubMedGoogle Scholar
  48. 48.
    Karlsson S, Bodine DM, Perry L, Papayannopoulou T, Nienhuis AW. Expression of the human β-globin gene following retroviral-mediated transfer into multipotential hematopoietic progenitors of mice. Proc Natl Acad Sci USA 85:6062–6066;1988.PubMedGoogle Scholar
  49. 49.
    Kay MA, Baley P, Rothenberg S, Leland F, Fleming L, Ponder KP, Liu T, Finegold M, Darlington G, Pokorny W, Woo SLC. Expression of human alpha 1-antitrypsin in dogs after autologous transplantation of retroviral transduced hepatocytes. Proc Natl Acad Sci USA 89:89–93;1992.PubMedGoogle Scholar
  50. 50.
    Keller G, Paige C, Gilboa E, Wagner EF. Expression of a foreign gene in myeloid and lymphoid cells derived from multipotent haematopoietic precursors. Nature 318:149–154;1985.CrossRefPubMedGoogle Scholar
  51. 51.
    Kempler G, Freitag B, Berwin B, Nanassy O, Barklis E. Characterization of the Moloney murine leukemia virus stem cell-specific repressor binding site. Virology 193:690–699;1993.CrossRefPubMedGoogle Scholar
  52. 52.
    Kiem H-P, Darovsky B, von Kalle C, Goehle S, Stewart D, Graham T, Hackman R, Appelbaum FR, Deeg HJ, Miller AD, Storb R, Schuening FG. Retrovirus-mediated gene transduction into canine periferal blood repopulating cells. Blood 83:1467–1473;1994.PubMedGoogle Scholar
  53. 53.
    Kohn DB. The current status of gene therapy using hematopoietic stem cells. Curr Opin Pediatr 7:56–63;1995.PubMedGoogle Scholar
  54. 54.
    Lang A, Fincham VJ, Wyke JA. Factors influencing physiological variations in the activity of the Rous sarcoma virus long terminal repeat. Virology 196:564–575;1993.CrossRefPubMedGoogle Scholar
  55. 55.
    Lewis JD, Meehan RR, Henzel WJ, Maurer Fogy I, Jeppesen P, Klein F, Bird A. Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69:905–914;1992.CrossRefPubMedGoogle Scholar
  56. 56.
    Licht T, Aksentijevich I, Gottesman MM, Pastan I. Efficient expression of functional human MDR1 gene in murine bone marrow after retroviral transduction of purified hematopoietic stem cells. Blood 86:111–121;1995.PubMedGoogle Scholar
  57. 57.
    Lichtenauer-Kaligis EGR, Van der Velde-van Dijke I, Den Hulk H, Van der Putte P, Giphart-Gassler M, Tasseronde Jong JG. Genomic position influences spontaneous mutagenesis of an integrated retroviral vector containing thehprt cDNA as target for mutagenesis. Hum Mol Genet 2:173–182;1993.PubMedGoogle Scholar
  58. 58.
    Lim B, Apperley JF, Orkin SH, Williams DA. Long-term expression of human adenosine deaminase in mice transplanted with retrovirus-infected hematopoietic stem cells. Proc Natl Acad Sci USA 86:8892–8896;1989.PubMedGoogle Scholar
  59. 59.
    Linney E, Davis B, Overhauser J, Chao E, Fan H. Non-function of a Moloney murine leukemia virus regulatory sequence in F9 embryonal carcinoma cells. Nature 308:470–472;1984.CrossRefPubMedGoogle Scholar
  60. 60.
    Linney E, Neill SD, Prestridge DS. Retroviral vector gene expression in F9 embryonal carcinoma cells. J Virol 61:3248–3253;1987.PubMedGoogle Scholar
  61. 61.
    Loh TP, Sievert LL, Scott RW. Evidence for a stem cell-specific repressor of Moloney murine leukemia virus in embryonal carcinoma cells. Mol Cell Biol 10:4045–4057;1990.PubMedGoogle Scholar
  62. 62.
    Loh TP, Sievert LL, Scott RW. Negative regulation of retrovirus expression in embryonal carcinoma cells mediated by an intragenic domain. J Virol 62:4086–4095;1988.PubMedGoogle Scholar
  63. 63.
    Loh TP, Sievert LL, Scott RW. Proviral sequences that restrict retroviral expression in mouse embryonal carcinoma cells. Mol Cell Biol 7:3775–3784;1987.PubMedGoogle Scholar
  64. 64.
    Lund AH, Duch M, Lovmand J, Jorgensen P, Pedersen FS. Mutated primer binding sites interacting with different tRNAs allow efficient murine leukemia virus replication. J Virol 67:7125–7130;1993.PubMedGoogle Scholar
  65. 65.
    Mann R, Mulligan RC, Baltimore D. Construction of a retrovirus packaging mutant and its use to produce helper-free defective retrovirus. Cell 33:153–159;1983.CrossRefPubMedGoogle Scholar
  66. 66.
    McCune SL, Townes TM. Retroviral vector sequences inhibit human beta-globin gene expression in transgenic mice. Nucleic Acids Res 22:4477–4481;1994.PubMedGoogle Scholar
  67. 67.
    McIvor RS, Johnson MJ, Miller AD, Pitts S, Williams SR, Valerio D, Martin DW Jr, Verma IM. Human purine nucleoside phosphorylase and adenosine deaminase: Gene transfer into cultured cells and murine hematopoietic stem cells by using recombinant amphotropic retroviruses. Mol Cell Biol 7:838–846;1987.PubMedGoogle Scholar
  68. 68.
    Meehan RR, Lewis JD, Bird AP. Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA. Nucleic Acids Res 20:5085–5092;1992.PubMedGoogle Scholar
  69. 69.
    Miller AD. Retrovirus packaging cells. Hum Gene Ther 1:5–14;1990.PubMedGoogle Scholar
  70. 70.
    Miller AD, Buttimore C. Redesign of retrovirus packaging cell lines to avoid recombination leading to helper virus production. Mol Cell Biol 6:2895–2902;1986.PubMedGoogle Scholar
  71. 71.
    Morgan RA, Couture L, Elroy Stein O, Ragheb J, Moss B, Anderson WF. Retroviral vectors containing putative internal ribosome entry sites: Development of a polycistronic gene transfer system and applications to human gene therapy. Nucleic Acids Res 20:1293–1299;1992.PubMedGoogle Scholar
  72. 72.
    Naldini L, Blomer U, Gallay P, Ory D, Mulligan R, Gage FH, Verma IM, Trono D. In vivo gene delivery and stable transduction of non-dividing cells by a lentiviral vector. Science 272:263–267;1996.PubMedGoogle Scholar
  73. 73.
    Niwa O, Yokota Y, Ishida H, Sugahara T. Independent mechanisms involved in suppression of the Moloney leukemia virus genome during differentiation of murine teratocarcinoma cells. Cell 32:1105–1113;1983.CrossRefPubMedGoogle Scholar
  74. 74.
    Nolta JA, Kohn DB. Comparison of the effects of growth factors on retroviral vector-mediated gene transfer and the proliferative status of human hematopoietic progenitor cells. Hum Gene Ther 1:257–268;1990.PubMedGoogle Scholar
  75. 75.
    Nolta JA, Hanley MB, Kohn DB. Sustained hematopoiesis in immunodeficient mice by cotransplantation of marrow stroma expressing human interleukin-3: Analysis of gene transduction of long-lived progenitors. Blood 83:3041–3051;1994.PubMedGoogle Scholar
  76. 76.
    Nolta JA, Smorgorzewska EM, Kohn DB. Analysis of optimal conditions for retroviral-mediated transduction of primitive human hematopoietic cells. Blood 86:101–110;1995.PubMedGoogle Scholar
  77. 77.
    Nolta JA, Dao MA, Wells S, Smogorzewska EM, Kohn DB. Transduction of pluripotent human hematopoietic stem cells demonstrated by clonal analysis after engraftment in immune-deficient mice. Proc Natl Acad Sci USA 93:2414–2419;1996.CrossRefPubMedGoogle Scholar
  78. 78.
    Novak U, Harris EA, Forrester W, Groudine M, Gelinas R. High-level beta-globin expression after retroviral transfer of locus activation region-containing human beta-globin gene derivatives into murine erythroleukemia cells. Proc Natl Acad Sci USA 87:3386–3390;1990.PubMedGoogle Scholar
  79. 79.
    Ohashi T, Boggs S, Robbins P, Bahnson A, Patrene K, Wei FS, Wei JF, Li J, Lucht L, Fei Y, Clark S, Kimak M, He H, Mowery-Rushton P, Barranger JA. Efficient transfer and sustained high expression of the human glucocere-brosidase gene in mice and their functional macrophages following transplantation of bone marrow transduced by a retroviral vector. Proc Natl Acad Sci USA 89:11332–11336;1992.PubMedGoogle Scholar
  80. 80.
    Palmer TD, Rosman GJ, Osborne WRA, Miller D. Genetically modified skin fibroblasts persist long after transplantation but gradually inactivate introduced genes. Proc Natl Acad Sci USA 88:1330–1334;1991.PubMedGoogle Scholar
  81. 81.
    Palmer TD, Thompson AR, Miller AD. Production of human factor IX in animals by genetically modified skin fibroblasts: Potential therapy for hemophilia B. Blood 73:438–445;1989.PubMedGoogle Scholar
  82. 82.
    Paludan K, Duch M, Jorgensen P, Kjeldgaard NO, Pedersen FS. Graduated resistance to G418 leads to differential selection of cultured cells expressing theneo gene. Gene 85:421–426;1989.CrossRefPubMedGoogle Scholar
  83. 83.
    Paludan K, Dai HY, Duch M, Jorgensen P, Kjeldgaard NO, Pedersen FS. Different relative expression from two murine leukemia virus long terminal repeats in unintegrated transfected DNA and in integrated retroviral vector proviruses. J Virol 63:5201–5207;1989.PubMedGoogle Scholar
  84. 84.
    Peckham I, Sobel S, Comer J, Jaenisch R, Barklis E. Retrovirus activation in embryonal carcinoma cells by cellular promoters. Genes Dev 3:2062–2071;1989.PubMedGoogle Scholar
  85. 85.
    Pedersen K, Lovmand S, Jorgensen EC, Pedersen FS, Jorgensen P. Efficient replication and expression of murine leukemia virus with major deletions in the enhancer region of U3. Virology 187:821–824;1992.CrossRefPubMedGoogle Scholar
  86. 86.
    Peters G, Harada F, Dahlberg JE, Panet A, Haseltine WA, Baltimore D. Low-molecular-weight RNAs of Moloney murine leukemia virus: Identification of the primer for RNA-directed DNA synthesis. J Virol 21:1031–1041;1977.PubMedGoogle Scholar
  87. 87.
    Petersen R, Kempler G, Barklis E. A stem cell-specific silencer in the primer-binding site of a retrovirus. Mol Cell Biol 11:1214–1221;1991.PubMedGoogle Scholar
  88. 88.
    Pierce GB, Podesta A, Wells RS. Malignancy and differentiation: The role of the blastocyst in control of colony formation. In: Teratoma Stem Cells. New York, CSH Conferences on Cell Proliferation 10:15–22;1983.Google Scholar
  89. 89.
    Prince VE, Rigby PW. Derivatives of Moloney murine sarcoma virus capable of being transcribed in embryonal carcinoma stem cells have gained a functional Sp1 binding site. J Virol 65:1803–1811;1991.PubMedGoogle Scholar
  90. 90.
    Ramesh N, Lau S, Palmer TD, Storb R, Osborne WR. High-level human adenosine deaminase expression in dog skin fibroblasts is not sustained following transplantation. Hum Gene Ther 4:3–7;1993.PubMedGoogle Scholar
  91. 91.
    Razin A, Cedar H. DNA methylation and gene expression. Microbiol Rev 55:451–458;1991.PubMedGoogle Scholar
  92. 92.
    Rettinger SD, Kennedy SC, Wu X, Saylors RL, Hafenrichter DG, Flye MW, Ponder KP. Liver-directed gene therapy: Quantitative evaluation of promoter elements by using in vivo retroviral transduction. Proc Natl Acad Sci USA 91:1460–1464;1994.PubMedGoogle Scholar
  93. 93.
    Richards CA, Huber BE. Generation of a transgenic model for retrovirus-mediated gene expression for hepatocellular carcinoma is thwarted by the lack of transgene expression. Hum Gene Ther 4:143–150;1993.PubMedGoogle Scholar
  94. 94.
    Riviere I, Brose K, Mulligan RC. Effects of retroviral vector design on expression of human adenosine deaminase in murine bone marrow transplant recipients engrafted with genetically modified cells. Proc Natl Acad Sci USA 92:6733–6737;1995.PubMedGoogle Scholar
  95. 95.
    Roe T, Reynolds TC, Yu G, Brown PO. Integration of murine leukemia virus DNA depends on mitosis. EMBO J 12:2099–2108;1993.PubMedGoogle Scholar
  96. 96.
    Rohdewohld H, Weiher H, Reik W, Jaenisch R, Breindl M. Retrovirus integration and chromatin structure: Moloney murine leukemia proviral integration sites map near DNase I-hypersensitive sites. J Virol 61:336–343;1987.PubMedGoogle Scholar
  97. 97.
    Rubenstein JLR, Nicolas J-F, Jacob F. Construction of a retrovirus capable of transducing and expressing genes in multipotential embryonic cells. Proc Natl Acad Sci USA 81:7137–7140;1984.PubMedGoogle Scholar
  98. 98.
    Sablitzky F, Jonsson JI, Cohen BL, Phillips RA. High frequency expression of integrated proviruses derived from enhancer trap retroviruses. Cell Growth Differ 4:451–459;1993.PubMedGoogle Scholar
  99. 99.
    Sadelain M, Wang CH, Antoniou M, Grosveld F, Mulligan RC. Generation of a high-titer retroviral vector capable of expressing high levels of the human beta-globin gene. Proc Natl Acad Sci USA 92:6728–6732;1995.PubMedGoogle Scholar
  100. 100.
    Scharfmann R, Axelrod JH, Verma IM. Long-term in vivo expression of retrovirus-mediated gene transfer in mouse fibroblast implants. Proc Natl Acad Sci USA 88:4626–4630;1991.PubMedGoogle Scholar
  101. 101.
    Sorge J, Cutting AE, Erdman VD, Gautsch JW. Integration-specific retrovirus expression in embryonal carcinoma cells. Proc Natl Acad Sci USA 81:6627–6631;1984.PubMedGoogle Scholar
  102. 102.
    Speck NA, Baltimore D. Six distinct nuclear factors interact with the 75-base-pair repeat of the Moloney murine leukemia virus enhancer. Mol Cell Biol 7:1101–1110;1987.PubMedGoogle Scholar
  103. 103.
    St Louis D, Verma IM. An alternative approach to somatic gene therapy. Proc Natl Acad Sci USA 85:3150–3154;1988.PubMedGoogle Scholar
  104. 104.
    Stewart CL, Schuetze S, Vanek M, Wagner EF. Expression of retroviral vectors in transgenic mice obtained by embryo infection. EMBO J 6:383–388;1987.PubMedGoogle Scholar
  105. 105.
    Stewart CL, Stuhlmann H, Jahner D, Jaenisch R. De novo methylation, expression, and infectivity of retroviral genomes introduced into embryonal carcinoma cells. Proc Natl Acad Sci USA 79:4098–4102;1982.PubMedGoogle Scholar
  106. 106.
    Stuhlmann H, Jahner D, Jaenisch R. Infectivity and methylation of retroviral genomes is correlated with expression in the animal. Cell 26:221–232;1981.CrossRefPubMedGoogle Scholar
  107. 107.
    Taketo M, Howard TA, Seldin MF. Mapping of recombinant retrovirus integration sites that cause expression of the viral genome in murine embryonal carcinoma cells. Mamm Genome 2:240–245;1992.CrossRefPubMedGoogle Scholar
  108. 108.
    Taketo M, Shaffer DJ. Deletions in a recombinant retrovirus genome associated with its expression in embryonal carcinoma cells. J Virol 63:4431–4433;1989.PubMedGoogle Scholar
  109. 109.
    Teich NM, Weiss RA, Martin GR, Lowy DR. Virus infection of murine teratocarcinoma stem cell lines. Cell 12:973–982;1977.CrossRefPubMedGoogle Scholar
  110. 110.
    Telesnitsky A, Goff SP. Strong stop transfer during reverse transcription. In: Skalka AM, Goff SP, eds. Reverse Transcriptase. New York, CSHL Press, 49–84;1993.Google Scholar
  111. 111.
    Tsukiyama T, Ueda H, Hirose S, Niwa O. Embryonal long terminal repeat-binding protein is the murine homologue of FTZ-F1, a member of the steroid receptor superfamily. Mol Cell Biol 12:1286–1291;1992.PubMedGoogle Scholar
  112. 112.
    Tsukiyama T, Niwa O, Yokoro K. Mechanisms of suppresion of the long terminal repeat of Moloney leukemia virus in mouse embryonal carcinoma cells. Mol Cell Biol 9:4670–4676;1989.PubMedGoogle Scholar
  113. 113.
    Valerio V, Einerhand MPW, Wamsley PM, Bakx TA, Verma IM. Retrovirus-mediated gene therapy into embryonal carcinoma and hematopoietic stem cells: Expression from a hybrid long terminal repeat. Gene 84:419–427;1989.CrossRefPubMedGoogle Scholar
  114. 114.
    Valerio D. Retrovirus vectors for gene therapy procedures. In: Grosveld F, Kollias G, eds. Transgenic Animals. Academic Press, 213–239;1992.Google Scholar
  115. 115.
    van Beusechem VW, Bakx TA, Kaptein LCM, Bart-Baumeister JAK, Kukler A, Braakman E, Valerio D. Retrovirus-mediated gene transfer into rhesus monkey hematopoietic stem cells: The effect of viral titers on transduction efficiency. Hum Gene Ther 4:239–247;1993.PubMedGoogle Scholar
  116. 116.
    van Beveren C, Coffin JM, Hughes S. Nucleotide sequences complemented with functional and structural analysis. In: Weiss R, Teich H, Varmus H, Coffin JM, eds. RNA Tumor Viruses. New York, CSHL Press, 790–805;1985.Google Scholar
  117. 117.
    Vijaya S, Steffen DL, Robinson HL. Acceptor sites for retroviral integrations map near DNase I-hypersensitive sites in chromatin. J Virol 60:683–692;1986.PubMedGoogle Scholar
  118. 118.
    Wagner EF, Vanek M, Vennström B. Transfer of genes into embryonal carcinoma cells by retrovirus infection: Efficient expression from an internal promoter. EMBO J 4:663–666;1985.PubMedGoogle Scholar
  119. 119.
    Wain Hobson S, Sonigo P, Danos O, Cole S, Alizon M. Nucleotide sequence of the AIDS virus, LAV. Cell 40:9–17;1985.CrossRefPubMedGoogle Scholar
  120. 120.
    Weiher H, Barklis E, Ostertag W, Jaenisch R. Two distinct sequence elements mediate retroviral gene expression in embryonal carcinoma cells. J Virol 61:2742–2746;1987.PubMedGoogle Scholar
  121. 121.
    Whitcomb JM, Hughes SH. Retroviral reverse transcription and integration: Process and problems. Annu Rev Cell Biol 8:275–306;1992.CrossRefPubMedGoogle Scholar
  122. 122.
    Williams DA, Lim B, Spooncer E, Longtine J, Dexter TM. Restriction of expression of an integrated recombinant retrovirus in primary but not immortalized murine hematopoietic stem cells. Blood 71:1738–1743;1988.PubMedGoogle Scholar
  123. 123.
    Williams DA, Orkin SH, Mulligan RC. Retrovirus-mediated transfer of human adenosine deaminase gene sequences into cells in culture and into murine hematopoietic cells in vivo. Proc Natl Acad Sci USA 83:2566–2570;1986.PubMedGoogle Scholar
  124. 124.
    Xu L, Yee JK, Wolff JA, Friedman T. Factors affecting long-term stability of Moloney murine leukemia virus-based vectors. Virology 171:331–341;1989.CrossRefPubMedGoogle Scholar
  125. 125.
    Yamauchi M, Freitag B, Khan C, Berwin B, Barklis E. Stem cell factor binding to retrovirus primer binding site silencers. J Virol 69:1142–1149;1995.PubMedGoogle Scholar

Copyright information

© National Science Council 1996

Authors and Affiliations

  • Anders H. Lund
    • 2
  • Mogens Duch
    • 2
  • Finn Skou Pedersen
    • 2
    • 1
  1. 1.Department of Medical Microbiology and ImmunologyUniversity of AarhusDenmark
  2. 2.Department of Molecular and Structural BiologyUniversity of AarhusAarhus CDenmark

Personalised recommendations