DOI QR코드

DOI QR Code

Retroviral integration profiles: their determinants and implications for gene therapy

  • Lim, Kwang-Il (Department of Medical and Pharmaceutical Sciences, College of Science, Sookmyung Women's University)
  • Received : 2011.02.06
  • Published : 2012.04.30

Abstract

Retroviruses have often been used for gene therapy because of their capacity for the long-term expression of transgenes via stable integration into the host genome. However, retroviral integration can also result in the transformation of normal cells into cancer cells, as demonstrated by the incidence of leukemia in a recent retroviral gene therapy trial in Europe. This unfortunate outcome has led to the rapid initiation of studies examining various biological and pathological aspects of retroviral integration. This review summarizes recent findings from these studies, including the global integration patterns of various types of retroviruses, viral and cellular determinants of integration, implications of integration for gene therapy and retrovirus-mediated infectious diseases, and strategies to shift integration to safe host genomic loci. A more comprehensive and mechanistic understanding of retroviral integration processes will eventually make it possible to generate safer retroviral vector platforms in the near future.

Keywords

References

  1. Coffin, J. M., Hughes, S. H. and Varmus, H. E. (1997) Retroviruses, Cold Spring Harbor Lab. Press, New York, U.S.A.
  2. Knipe, D. M. and Howley, P. M. (2006) Fields Virology, 5th ed., Lippincott Williams & Wilkins, Philadelphia, USA.
  3. Doi, K., Wu, X., Taniguchi, Y., Yasunaga, J., Satou, Y., Okayama, A., Nosaka, K. and Matsuoka, M. (2005) Preferential selection of human T-cell leukemia virus type I provirus integration sites in leukemic versus carrier states. Blood 106, 1048-1053. https://doi.org/10.1182/blood-2004-11-4350
  4. Guss, D. A. (1994) The acquired immune deficiency syndrome: an overview for the emergency physician, Part 2. J. Emerg. Med. 12, 491-497. https://doi.org/10.1016/0736-4679(94)90346-8
  5. Guss, D. A. (1994) The acquired immune deficiency syndrome: an overview for the emergency physician, Part 1. J. Emerg. Med. 12, 375-384. https://doi.org/10.1016/0736-4679(94)90281-X
  6. Fan, H. (2007) A new human retrovirus associated with prostate cancer. Proc. Natl. Acad. Sci. U.S.A. 104, 1449-1450. https://doi.org/10.1073/pnas.0610912104
  7. Shimotohno, K. and Temin, H. M. (1982) Loss of intervening sequences in genomic mouse alpha-globin DNA inserted in an infectious retrovirus vector. Nature 299, 265-268. https://doi.org/10.1038/299265a0
  8. Watanabe, S. and Temin, H. M. (1983) Construction of a helper cell line for avian reticuloendotheliosis virus cloning vectors. Mol. Cell. Biol. 3, 2241-2249. https://doi.org/10.1128/MCB.3.12.2241
  9. Schaffer, D. V., Koerber, J. T. and Lim, K. I. (2008) Molecular engineering of viral gene delivery vehicles. Annu. Rev. Biomed. Eng. 10, 169-194. https://doi.org/10.1146/annurev.bioeng.10.061807.160514
  10. Schambach, A. and Baum, C. (2008) Clinical application of lentiviral vectors - concepts and practice. Curr. Gene Ther. 8, 474-482. https://doi.org/10.2174/156652308786848049
  11. 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., Sorensen, R., Forster, A., Fraser, P., Cohen, J. I., de Saint Basile, G., Alexander, I., Wintergerst, U., Frebourg, T., Aurias, A., Stoppa-Lyonnet, D., Romana, S., Radford-Weiss, I., Gross, F., Valensi, F., Delabesse, E., Macintyre, E., Sigaux, F., Soulier, J., Leiva, L. E., Wissler, M., Prinz, C., Rabbitts, T. H., Le Deist, F., Fischer, A. and Cavazzana-Calvo, M. (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302, 415-419. https://doi.org/10.1126/science.1088547
  12. Cavazzana-Calvo, M., Payen, E., Negre, O., Wang, G., Hehir, K., Fusil, F., Down, J., Denaro, M., Brady, T., Westerman, K., Cavallesco, R., Gillet-Legrand, B., Caccavelli, L., Sgarra, R., Maouche-Chretien, L., Bernaudin, F., Girot, R., Dorazio, R., Mulder, G. J., Polack, A., Bank, A., Soulier, J., Larghero, J., Kabbara, N., Dalle, B., Gourmel, B., Socie, G., Chretien, S., Cartier, N., Aubourg, P., Fischer, A., Cornetta, K., Galacteros, F., Beuzard, Y., Gluckman, E., Bushman, F., Hacein-Bey-Abina, S. and Leboulch, P. (2010) Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature 467, 318-322. https://doi.org/10.1038/nature09328
  13. Aiuti, A., Slavin, S., Aker, M., Ficara, F., Deola, S., Mortellaro, A., Morecki, S., Andolfi, G., Tabucchi, A., Carlucci, F., Marinello, E., Cattaneo, F., Vai, S., Servida, P., Miniero, R., Roncarolo, M. G. and Bordignon, C. (2002) Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 296, 2410-2413. https://doi.org/10.1126/science.1070104
  14. Ott, M. G., Schmidt, M., Schwarzwaelder, K., Stein, S., Siler, U., Koehl, U., Glimm, H., Kuhlcke, K., Schilz, A., Kunkel, H., Naundorf, S., Brinkmann, A., Deichmann, A., Fischer, M., Ball, C., Pilz, I., Dunbar, C., Du, Y., Jenkins, N. A., Copeland, N. G., Luthi, U., Hassan, M., Thrasher, A. J., Hoelzer, D., von Kalle, C., Seger, R. and Grez, M. (2006) Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat. Med. 12, 401-409. https://doi.org/10.1038/nm1393
  15. Takahashi, K. and Yamanaka, S. (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676. https://doi.org/10.1016/j.cell.2006.07.024
  16. Wu, X., Li, Y., Crise, B. and Burgess, S. M. (2003) Transcription start regions in the human genome are favored targets for MLV integration. Science 300, 1749-1751. https://doi.org/10.1126/science.1083413
  17. Lim, K. I., Klimczak, R., Yu, J. H. and Schaffer, D. V. (2010) Specific insertions of zinc finger domains into Gag-Pol yield engineered retroviral vectors with selective integration properties. Proc. Natl. Acad. Sci. U.S.A. 107, 12475-12480. https://doi.org/10.1073/pnas.1001402107
  18. Tsukahara, T., Agawa, H., Matsumoto, S., Matsuda, M., Ueno, S., Yamashita, Y., Yamada, K., Tanaka, N., Kojima, K. and Takeshita, T. (2006) Murine leukemia virus vector integration favors promoter regions and regional hot spots in a human T-cell line. Biochem. Biophys. Res. Commun. 345, 1099-1107. https://doi.org/10.1016/j.bbrc.2006.05.007
  19. Hematti, P., Hong, B. K., Ferguson, C., Adler, R., Hanawa, H., Sellers, S., Holt, I. E., Eckfeldt, C. E., Sharma, Y., Schmidt, M., von Kalle, C., Persons, D. A., Billings, E. M., Verfaillie, C. M., Nienhuis, A. W., Wolfsberg, T. G., Dunbar, C. E. and Calmels, B. (2004) Distinct genomic integration of MLV and SIV vectors in primate hematopoietic stem and progenitor cells. PLoS Biol. 2, e423. https://doi.org/10.1371/journal.pbio.0020423
  20. Maruggi, G., Porcellini, S., Facchini, G., Perna, S. K., Cattoglio, C., Sartori, D., Ambrosi, A., Schambach, A., Baum, C., Bonini, C., Bovolenta, C., Mavilio, F. and Recchia, A. (2009) Transcriptional enhancers induce insertional gene deregulation independently from the vector type and design. Mol. Ther. 17, 851-856. https://doi.org/10.1038/mt.2009.51
  21. Beard, B. C., Dickerson, D., Beebe, K., Gooch, C., Fletcher, J., Okbinoglu, T., Miller, D. G., Jacobs, M. A., Kaul, R., Kiem, H. P. and Trobridge, G. D. (2007) Comparison of HIV-derived lentiviral and MLV-based gammaretroviral vector integration sites in primate repopulating cells. Mol. Ther. 15, 1356-1365. https://doi.org/10.1038/sj.mt.6300159
  22. Felice, B., Cattoglio, C., Cittaro, D., Testa, A., Miccio, A., Ferrari, G., Luzi, L., Recchia, A. and Mavilio, F. (2009) Transcription factor binding sites are genetic determinants of retroviral integration in the human genome. PLoS One. 4, e4571. https://doi.org/10.1371/journal.pone.0004571
  23. Moalic, Y., Felix, H., Takeuchi, Y., Jestin, A. and Blanchard, Y. (2009) Genome areas with high gene density and CpG island neighborhood strongly attract porcine endogenous retrovirus for integration and favor the formation of hot spots. J. Virol. 83, 1920-1929. https://doi.org/10.1128/JVI.00856-08
  24. Kim, S., Kim, N., Dong, B., Boren, D., Lee, S. A., Das Gupta, J., Gaughan, C., Klein, E. A., Lee, C., Silverman, R. H. and Chow, S. A. (2008) Integration site preference of xenotropic murine leukemia virus-related virus, a new human retrovirus associated with prostate cancer. J. Virol. 82, 9964-9977. https://doi.org/10.1128/JVI.01299-08
  25. Schroder, A. R., Shinn, P., Chen, H., Berry, C., Ecker, J. R. and Bushman, F. (2002) HIV-1 integration in the human genome favors active genes and local hotspots. Cell 110, 521-529. https://doi.org/10.1016/S0092-8674(02)00864-4
  26. Mitchell, R. S., Beitzel, B. F., Schroder, A. R., Shinn, P., Chen, H., Berry, C. C., Ecker, J. R. and Bushman, F. D. (2004) Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol. 2, E234. https://doi.org/10.1371/journal.pbio.0020234
  27. Ciuffi, A., Mitchell, R. S., Hoffmann, C., Leipzig, J., Shinn, P., Ecker, J. R. and Bushman, F. D. (2006) Integration site selection by HIV-based vectors in dividing and growth-arrested IMR-90 lung fibroblasts. Mol. Ther. 13, 366-373. https://doi.org/10.1016/j.ymthe.2005.10.009
  28. Crise, B., Li, Y., Yuan, C., Morcock, D. R., Whitby, D., Munroe, D. J., Arthur, L. O. and Wu, X. (2005) Simian immunodeficiency virus integration preference is similar to that of human immunodeficiency virus type 1. J. Virol. 79, 12199-12204. https://doi.org/10.1128/JVI.79.19.12199-12204.2005
  29. Monse, H., Laufs, S., Kuate, S., Zeller, W. J., Fruehauf, S. and Uberla, K. (2006) Viral determinants of integration site preferences of simian immunodeficiency virus-based vectors. J. Virol. 80, 8145-8150. https://doi.org/10.1128/JVI.00373-06
  30. Montini, E., Cesana, D., Schmidt, M., Sanvito, F., Ponzoni, M., Bartholomae, C., Sergi Sergi, L., Benedicenti, F., Ambrosi, A., Di Serio, C., Doglioni, C., von Kalle, C. and Naldini, L. (2006) Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. Nat. Biotechnol. 24, 687-696. https://doi.org/10.1038/nbt1216
  31. Nowrouzi, A., Dittrich, M., Klanke, C., Heinkelein, M., Rammling, M., Dandekar, T., von Kalle, C. and Rethwilm, A. (2006) Genome-wide mapping of foamy virus vector integrations into a human cell line. J. Gen. Virol. 87, 1339-1347. https://doi.org/10.1099/vir.0.81554-0
  32. Meekings, K. N., Leipzig, J., Bushman, F. D., Taylor, G. P. and Bangham, C. R. (2008) HTLV-1 integration into transcriptionally active genomic regions is associated with proviral expression and with HAM/TSP. PLoS Pathog. 4, e1000027. https://doi.org/10.1371/journal.ppat.1000027
  33. Gillet, N. A., Malani, N., Melamed, A., Gormley, N., Carter, R., Bentley, D., Berry, C., Bushman, F. D., Taylor, G. P. and Bangham, C. R. (2011) The host genomic environment of the provirus determines the abundance of HTLV-1-infected T-cell clones. Blood 117, 3113-3122. https://doi.org/10.1182/blood-2010-10-312926
  34. Lewinski, M. K., Yamashita, M., Emerman, M., Ciuffi, A., Marshall, H., Crawford, G., Collins, F., Shinn, P., Leipzig, J., Hannenhalli, S., Berry, C. C., Ecker, J. R. and Bushman, F. D. (2006) Retroviral DNA integration: viral and cellular determinants of target-site selection. PLoS Pathog. 2, e60. https://doi.org/10.1371/journal.ppat.0020060
  35. Appa, R. S., Shin, C. G., Lee, P. and Chow, S. A. (2001) Role of the nonspecific DNA-binding region and alpha helices within the core domain of retroviral integrase in selecting target DNA sites for integration. J. Biol. Chem. 276, 45848-45855. https://doi.org/10.1074/jbc.M107365200
  36. Maertens, G. N., Hare, S. and Cherepanov, P. (2010) The mechanism of retroviral integration from X-ray structures of its key intermediates. Nature 468, 326-329. https://doi.org/10.1038/nature09517
  37. Studamire, B. and Goff, S. P. (2008) Host proteins interacting with the Moloney murine leukemia virus integrase: multiple transcriptional regulators and chromatin binding factors. Retrovirology. 5, 48. https://doi.org/10.1186/1742-4690-5-48
  38. Ciuffi, A., Llano, M., Poeschla, E., Hoffmann, C., Leipzig, J., Shinn, P., Ecker, J. R. and Bushman, F. (2005) A role for LEDGF/p75 in targeting HIV DNA integration. Nat. Med. 11, 1287-1289. https://doi.org/10.1038/nm1329
  39. Shun, M. C., Raghavendra, N. K., Vandegraaff, N., Daigle, J. E., Hughes, S., Kellam, P., Cherepanov, P. and Engelman, A. (2007) LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev. 21, 1767-1778. https://doi.org/10.1101/gad.1565107
  40. Ocwieja, K. E., Brady, T. L., Ronen, K., Huegel, A., Roth, S. L., Schaller, T., James, L. C., Towers, G. J., Young, J. A., Chanda, S. K., Konig, R., Malani, N., Berry, C. C. and Bushman, F. D. (2011) HIV integration targeting: a pathway involving Transportin-3 and the nuclear pore protein RanBP2. PLoS Pathog. 7, e1001313. https://doi.org/10.1371/journal.ppat.1001313
  41. Konig, R., Zhou, Y., Elleder, D., Diamond, T. L., Bonamy, G. M., Irelan, J. T., Chiang, C. Y., Tu, B. P., De Jesus, P. D., Lilley, C. E., Seidel, S., Opaluch, A. M., Caldwell, J. S., Weitzman, M. D., Kuhen, K. L., Bandyopadhyay, S., Ideker, T., Orth, A. P., Miraglia, L. J., Bushman, F. D., Young, J. A. and Chanda, S. K. (2008) Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell 135, 49-60. https://doi.org/10.1016/j.cell.2008.07.032
  42. Wang, G. P., Ciuffi, A., Leipzig, J., Berry, C. C. and Bushman, F. D. (2007) HIV integration site selection: analysis by massively parallel pyrosequencing reveals association with epigenetic modifications. Genome Res. 17, 1186-1194. https://doi.org/10.1101/gr.6286907
  43. Tan, W., Dong, Z., Wilkinson, T. A., Barbas, C. F.,3rd and Chow, S. A. (2006) 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. 80, 1939-1948. https://doi.org/10.1128/JVI.80.4.1939-1948.2006
  44. Katz, R. A., Merkel, G. and Skalka, A. M. (1996) Targeting of retroviral integrase by fusion to a heterologous DNA binding domain: in vitro activities and incorporation of a fusion protein into viral particles. Virology. 217, 178-190. https://doi.org/10.1006/viro.1996.0105
  45. Goulaouic, H. and Chow, S. A. (1996) Directed integration of viral DNA mediated by fusion proteins consisting of human immunodeficiency virus type 1 integrase and Escherichia coli LexA protein. J. Virol. 70, 37-46.
  46. Bushman, F. D. (1994) Tethering human immunodeficiency virus 1 integrase to a DNA site directs integration to nearby sequences. Proc. Natl. Acad. Sci. U.S.A. 91, 9233-9237. https://doi.org/10.1073/pnas.91.20.9233
  47. Philippe, S., Sarkis, C., Barkats, M., Mammeri, H., Ladroue, C., Petit, C., Mallet, J. and Serguera, C. (2006) Lentiviral vectors with a defective integrase allow efficient and sustained transgene expression in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A. 103, 17684-17689. https://doi.org/10.1073/pnas.0606197103
  48. 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., Duran, Y., Bartholomae, C., von Kalle, C., Heckenlively, J. R., Kinnon, C., Ali, R. R. and Thrasher, A. J. (2006) Effective gene therapy with nonintegrating lentiviral vectors. Nat. Med. 12, 348-353. https://doi.org/10.1038/nm1365
  49. Cattoglio, C., Pellin, D., Rizzi, E., Maruggi, G., Corti, G., Miselli, F., Sartori, D., Guffanti, A., Di Serio, C., Ambrosi, A., De Bellis, G. and Mavilio, F. (2010) High-definition mapping of retroviral integration sites identifies active regulatory elements in human multipotent hematopoietic progenitors. Blood 116, 5507-5517. https://doi.org/10.1182/blood-2010-05-283523

Cited by

  1. Suicide HSVtk Gene Delivery by Neurotensin-Polyplex Nanoparticles via the Bloodstream and GCV Treatment Specifically Inhibit the Growth of Human MDA-MB-231 Triple Negative Breast Cancer Tumors Xenografted in Athymic Mice vol.9, pp.5, 2014, https://doi.org/10.1371/journal.pone.0097151
  2. Non-viral gene therapy for bone tissue engineering vol.29, pp.2, 2013, https://doi.org/10.1080/02648725.2013.801227
  3. Efficient transduction of LEDGF/p75 mutant cells by complementary gain-of-function HIV-1 integrase mutant viruses vol.1, 2014, https://doi.org/10.1038/mtm.2013.2
  4. Regulation of human GDNF gene expression in nigral dopaminergic neurons using a new doxycycline-regulated NTS-polyplex nanoparticle system vol.13, pp.4, 2017, https://doi.org/10.1016/j.nano.2017.02.006
  5. Optimizing NTS-Polyplex as a Tool for Gene Transfer to Cultured Dopamine Neurons vol.7, pp.12, 2012, https://doi.org/10.1371/journal.pone.0051341
  6. Recent advances in developing molecular tools for targeted genome engineering of mammalian cells vol.48, pp.1, 2015, https://doi.org/10.5483/BMBRep.2015.48.1.165
  7. Baculovirus: an Insect-derived Vector for Diverse Gene Transfer Applications vol.21, pp.4, 2013, https://doi.org/10.1038/mt.2012.286
  8. Neurotensin-polyplex-mediated brain-derived neurotrophic factor gene delivery into nigral dopamine neurons prevents nigrostriatal degeneration in a rat model of early Parkinson’s disease vol.22, pp.1, 2015, https://doi.org/10.1186/s12929-015-0166-7
  9. Applications of DNA integrating elements: Facing the bias bully vol.4, pp.6, 2014, https://doi.org/10.4161/2159256X.2014.992694
  10. Molecular mechanisms of retroviral integration site selection vol.42, pp.16, 2014, https://doi.org/10.1093/nar/gku769
  11. High-performance method for specific effect on nucleic acids in cells using TiO2~DNA nanocomposites vol.2, pp.1, 2012, https://doi.org/10.1038/srep00756