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Integration Site Selection by Lentiviruses: Biology and Possible Control

  • Chapter
Lentiviral Vectors

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 261))

Abstract

Retroviral vectors are popular vehicles for gene transfer, since they neatly integrate a single copy of a new gene into a transduced cell. The viral cDNA that becomes integrated is colinear with the vector genome, yielding a predictable final product. Gene transfer by transfection of naked DNA, in contrast, leads to the formation of scrambled arrays of new sequences that are often unstable and unpredictable in their behavior. Retroviral cDNA integration is sequence nonspecific with respect to the choice of target site; however, this raises a variety of issues surrounding the safety and effectiveness of retroviral vectors. This chapter first covers studies of target site selection by retroviruses, particularly HIV-1, and then the efforts being made to control target site selection in vivo.

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References

  • Bor Y-C, Bushman F, Orgel L (1995) In vitro integration of human immunodeficiency virus type 1 cDNA into targets containing protein-induced bends. Proc Natl Acad Sci USA 92:10334–10338

    Article  PubMed  CAS  Google Scholar 

  • Bor Y-C, Miller M, Bushman F, Orgel L (1996) Target sequence preferences of HIV-1 integration complexes in vitro. Virology 222:238–242

    Article  Google Scholar 

  • Bushman F, Miller MD (1997) Tethering human immunodeficiency virus type 1 preintegration complexes to target DNA promotes integration at bearby sites. J Virol 71:458–464

    PubMed  CAS  Google Scholar 

  • Bushman FD (1994) Tethering human immunodeficiency virus 1 integrase to a DNA site directs integration to nearby sequences. Proc Natl Acad Sci USA 91:9233–9237

    Article  PubMed  CAS  Google Scholar 

  • Bushman FD (1995) Targeting retroviral integration. Science 267:1443–1444

    Article  PubMed  CAS  Google Scholar 

  • Bushman FD, Craigie R (1990) Sequence requirements for integration of Moloney murine leukemia virus DNA in vitro. J Virol 64:5645–5648

    PubMed  CAS  Google Scholar 

  • Bushman FD, Craigie R (1991) Activities of human immunodeficiency virus (HIV) integration protein in vitro: Specific cleavage and integration of HIV DNA. Proc Natl Acad Sci USA 88:1339–1343

    Article  PubMed  CAS  Google Scholar 

  • Bushman FD, Craigie R (1992) Integration of human immunodeficiency virus DNA: adduct interference analysis of required DNA sites. Proc Natl Acad Sci USA 89:3458–3462

    Article  PubMed  CAS  Google Scholar 

  • Bushman FD, Fujiwara T, Craigie R (1990) Retroviral DNA integration directed by HIV integration protein in vitro. Science 249:1555–1558

    Article  PubMed  CAS  Google Scholar 

  • Carteau S, Hoffmann C, Bushman FD (1998) Chromosome structure and HIV-1 cDNA integration: centromeric alphoid repeats are a disfavored target. J Virol 72:4005–4014

    PubMed  CAS  Google Scholar 

  • Chalker DL, Sandmeyer SB (1992) Ty3 integrates within the region of RNA polymerase III transcription initiation. Genes Dev 6:117–128

    Article  PubMed  CAS  Google Scholar 

  • Choo Y, Klug A (1994a) Selection of DNA binding sites for zinc fingers using rationally randomized DNA reveals coded interactions. Proc Natl Acad Sci USA 91:11168–11172

    Article  PubMed  CAS  Google Scholar 

  • Choo Y, Klug A (1994b) Toward a code for the interactions of zinc fingers with DNA: selection of randomized fingers displayed on phage. Proc Natl Acad Sci USA 91:11163–11167

    Article  PubMed  CAS  Google Scholar 

  • Coffin JM (1990) Retroviridae and their replication. In: Fields BN, Kinpe DM (eds) Virology, (New York, Raven Press), pp 1437–1500

    Google Scholar 

  • Coffin JM, Hughes SH, Varmus HE (1997) Retroviruses (Cold Spring Harbor, Cold Spring Harbor Laboratory Press)

    Google Scholar 

  • Craigie R, Fujiwara T, Bushman F (1990) The IN protein of Moloney murine leukemia virus processes the viral DNA ends and accomplishes their integration in vitro. Cell 62:829–837

    Article  PubMed  CAS  Google Scholar 

  • Desjarlais JR, Berg JM (1994) Length-encoded multiplex binding site determination: Application to zinc finger proteins. Proc Natl Acad Sci USA 91:11099–11103

    Article  PubMed  CAS  Google Scholar 

  • Fitzgerald ML, Grandgenett DP (1994) Retroviral integration: in vitro host site selection by avian integrase. J Virol 68:4314–4321

    PubMed  CAS  Google Scholar 

  • Fletcher TM, Soares MA, McPhearson S, Hui H, Wiskerchen M, Muesing MA, Shaw GM, Leavitt AD, Boeke JD, Hahn BH (1997) Complementation of integrase functions in HIV-1 virions. EMBO J 16:5123–5138

    Article  PubMed  CAS  Google Scholar 

  • Goodarzi G, Chiu R, Brackmann K, Kohn K, Pommier Y, Grandgenett DP (1997) Host site selection for concerted integration by human immunodeficiency virus type-1 virions in vitro. Virology 231:210–217

    Article  PubMed  CAS  Google Scholar 

  • Goulaouic H, Chow SA (1996) Directed integration of viral DNA mediated by fusion proteins consisting of himan immunodeficiency virus type 1 integrase and Escherichia coliLexA protein. J Virol 70:37–46

    PubMed  CAS  Google Scholar 

  • Hansen MST, Carteau S, Hoffmann C, Li L, Bushman F (1998) Retroviral cDNA integration: mechanism, applications and inhibition. In: Setlow JK (ed) Genetic Engineering. Principles and Methods, (New York and London, Plenum Press), pp 41–62

    Google Scholar 

  • Holmes-Son ML, Chow SA (2000) Integrase-lexA fusion proteins incorporated into human immunodeficiency virus type 1 that contain a catalytically inactive integrase gene are functional to mediate integration. J Virol 74:11548–11556

    Article  PubMed  CAS  Google Scholar 

  • Howard MT, Griffith JD (1993) A cluster of strong topoisomerase II cleavage sites is located near an integrated human immunodeficiency virus. J Mol Biol 232:1060–1068

    Article  PubMed  CAS  Google Scholar 

  • Ji H, Moore DP, Blomberg MA, Braiterman LT, Voytas DF, Natsoulis G, Boeke JD (1993) Hotspots for unselected tyl transposition events on yeast chromosome III are near tRNA genes and LTR sequences. Cell 73:1–20

    Article  Google Scholar 

  • Katz RA, Merkel G, Skalka AM (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

    Article  PubMed  CAS  Google Scholar 

  • Katzman M, Katz RA, Skalka AM, Leis J (1989) The avian retroviral integration protein cleaves the terminal sequences of linear viral DNA at the in vivo sites of integration. J Virol 63:5319–5327

    PubMed  CAS  Google Scholar 

  • Kim J-S, Pabo CO (1998) Getting a handhold on DNA: design of poly-zinc finger proteins with femptomolar dissociation constants. Proc Natl Acad Sci USA 95:2812–2817

    Article  PubMed  CAS  Google Scholar 

  • Kirchner J, Connolly CM, Sandmeyer SB (1995) In vitro position-specific integration of a retrovirus-like element requires Pol III transcription factors. Science 267:1488–1491

    Article  PubMed  CAS  Google Scholar 

  • Leclercq I, Mortreux F, Cavrois M, Leroy A, Gessain A, Wain-Hobson S, Wattel E (2000) Host sequences flanking the human T-Cell leukemia virus type 1 provirus in vivo. J Virol 74:2305–2312

    Article  PubMed  CAS  Google Scholar 

  • Miller M, Bor Y-C, Bushman FD (1995) Target DNA capture by HIV-1 integration complexes. Curr Biol 5:1047–1056

    Article  PubMed  CAS  Google Scholar 

  • Miller MD, Farnet CM, Bushman FD (1997) Human immunodeficiency virus type 1 preintegration complexes: studies of organization and composition. J Virol 71:5382–5390

    PubMed  CAS  Google Scholar 

  • Milot E, Belmaaza A, Rassart E, Chartrand P (1994) Association of a host DNA structure with retroviral integration sites in chromosomal DNA. Virology 201:408–412

    Article  PubMed  CAS  Google Scholar 

  • Muller H-P, Varmus HE (1994) DNA bending creates favored sites for retroviral integration: an explanation for preferred insertion sites in nucleosomes. EMBO J 13:4704–4714

    PubMed  CAS  Google Scholar 

  • Patel PH, Preston BD (1994) Marked infidelity of human immunodeficiency virus type 1 reverse transcriptase at RNA and DNA template ends. Proc Natl Acad Sci USA 91:549–553

    Article  PubMed  CAS  Google Scholar 

  • Pruss D, Bushman FD, Wolffe AP (1994a) Human immunodeficiency virus integrase directs integration to sites of severe DNA distortion within the nucleosome core. Proc Natl Acad Sci USA 91:5913–5917

    Article  PubMed  CAS  Google Scholar 

  • Pruss D, Reeves R, Bushman FD, Wolffe AP (1994b) The influence of DNA and nucleosome structure on integration events directed by HIV integrase. J Biol Chem 269:25031–25041

    PubMed  CAS  Google Scholar 

  • Pryciak P, Muller H-P, Varmus HE (1992a) Simian virus 40 minichromosomes as targets for retroviral integration in vivo. Proc Natl Acad Sci USA 89:9237–9241

    Article  PubMed  CAS  Google Scholar 

  • Pryciak PM, Sil A, Varmus HE (1992b) Retroviral integration into minichromosomes in vitro. EMBO J 11:291–303

    PubMed  CAS  Google Scholar 

  • Pryciak PM, Varmus HE (1992) Nucleosomes, DNA-binding proteins, and DNA sequence modulate retroviral integration target site selection. Cell 69:769–780

    Article  PubMed  CAS  Google Scholar 

  • Rebar EJ, Pabo CO (1994) Zinc finger phage: affinity selection of fingers with new DNA-binding specificities. Science 263:671–673

    Article  PubMed  CAS  Google Scholar 

  • Rohdewohld H, Weiher H, Reik W, Jaenisch R, Breindl M (1987) Retrovirus integration and chromatin structure: moloney murine leukemia proviral integration sites map near DNase I-hypersensitive sites. J Virol 61:336

    PubMed  CAS  Google Scholar 

  • Scherdin U, Rhodes K, Breindl M (1990) Transcriptionally active genome regions are preferred targets for retrovirus integration. J Virol 64:907

    PubMed  CAS  Google Scholar 

  • Scottoline BP, Chow S, Ellison V, Brown PO (1997) Disruption of the terminal base pairs of retroviral DNA during integration. Genes Dev 11:371–382

    Article  PubMed  CAS  Google Scholar 

  • Sherman PA, Fyfe JA (1990) Human immunodeficiency virus integration protein expressed in Escherichia colipossesses selective DNA cleaving activity. Proc Natl Acad Sci USA 87:5119–5123

    Article  PubMed  CAS  Google Scholar 

  • Shih C-C, Stoye JP, Coffin JM (1988) Highly preferred targets for retrovirus integration. Cell 53:531–537

    Article  PubMed  CAS  Google Scholar 

  • Shiramizu B, Herndier BG, McGrath MS (1994) Identification of a common clonal human immunodeficiency virus integration site in human immunodeficiency virus-associated lymphomas. Cancer Res 54:2069–2072

    PubMed  CAS  Google Scholar 

  • Stevens SW, Griffith JD (1994) Human immunodeficiency virus type 1 may preferentially integrate into chromatin occupied by LIHs repetitive elements. Proc Natl Acad Sci USA 91:5557–5561

    Article  PubMed  CAS  Google Scholar 

  • Stevens SW, Griffith JD (1996) Sequence analysis of the human DNA flanking sites of human immunodeficiency virus type 1 Integration. J Virol 70:6459–6462

    PubMed  CAS  Google Scholar 

  • Vijaya S, Steffan DL, Robinson HL (1986) Acceptor Sites for retroviral integrations map near DNasel-hypersensitive sites in chromatin. J Virol 60:683–692

    PubMed  CAS  Google Scholar 

  • Weidhaas JB, Angelichio EL, Fenner S, Coffin JM (2000) Relationship between retroviral DNA integration and gene expression. J Virol 74:8382–8389

    Article  PubMed  CAS  Google Scholar 

  • Withers-Ward ES, Kitamura Y, Barnes JP, Coffin JM (1994) Distribution of targets for avian retrovirus DNA integration in vivo. Genes Dev 8:1473–1487

    Article  PubMed  CAS  Google Scholar 

  • Wu H, Yang W-P, Barbas CF (1995a) Building zinc fingers by selection: toward a therapeutic application. Proc Natl Acad Sci USA 92:344–348

    Article  PubMed  CAS  Google Scholar 

  • Wu X, Liu H, Xiao H, Kim J, Seshaiah P, Natsoulis G, Boeke JD, Hahn BH, Kappes JC (1995b) Targeting foreign proteins to human immunodeficiencyy virus particles via fusion with Vpr and Vpx. J Virol 69:3389–3398

    PubMed  CAS  Google Scholar 

  • Yoder K, Bushman FD (2000) Repair of gaps in retroviral DNA integration intermediates. J Virol 74:11191–11200

    Article  PubMed  CAS  Google Scholar 

  • Zou S, Voytas DF (1997) Silent chromatin determines target preferences of the Saccharomyces retrotransposon Ty5. Proc Natl Acad Sci USA 94:7412–7416

    Article  PubMed  CAS  Google Scholar 

  • Zou S, Wright DA, Voytas DF (1995) The Saccharomyces Ty5 retrotransposon family is associated with origins of DNA replication at the telomeres and the silent mating locus HMR. Proc Natl Acad Sci USA 92:920–924

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Infectious Disease Laboratory, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA

    F. D. Bushman

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  1. F. D. Bushman
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Editors and Affiliations

  1. Department of Genetics and Microbiology, Faculty of Medicine, University of Geneva, CMU; 1 rue Michel-Servet, 1211, Geneva 4, Switzerland

    Didier Trono

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© 2002 Springer-Verlag Berlin Heidelberg

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Bushman, F.D. (2002). Integration Site Selection by Lentiviruses: Biology and Possible Control. In: Trono, D. (eds) Lentiviral Vectors. Current Topics in Microbiology and Immunology, vol 261. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-56114-6_8

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  • DOI: https://doi.org/10.1007/978-3-642-56114-6_8

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-62667-8

  • Online ISBN: 978-3-642-56114-6

  • eBook Packages: Springer Book Archive

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