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(Strept)avidin-displaying lentiviruses as versatile tools for targeting and dual imaging of gene delivery

Abstract

Lentiviruses have shown great promise for human gene therapy. However, no optimal strategies are yet available for noninvasive imaging of virus biodistribution and subsequent transduction in vivo. We have developed a dual-imaging strategy based on avidin–biotin system allowing easy exchange of the surface ligand on HIV-derived lentivirus envelope. This was achieved by displaying avidin or streptavidin fused to the transmembrane anchor of vesicular stomatitis virus G protein on gp64-pseudotyped envelopes. Avidin and streptavidin were efficiently incorporated on virus particles, which consequently showed binding to biotin in ELISA. These vectors, conjugated to biotinylated radionuclides and engineered to express a ferritin transgene, enabled for the first-time dual imaging of virus biodistribution and transduction pattern by single-photon emission computed tomography and magnetic resonance imaging after stereotactic injection into rat brain. In addition, vector retargeting to cancer cells overexpressing CD46, epidermal growth factor and transferrin receptors using biotinylated ligands and antibodies was demonstrated in vitro. In conclusion, we have generated novel lentivirus vectors for noninvasive imaging and targeting of lentivirus-mediated gene delivery. This study suggests that these novel vectors could be applicable for the treatment of central nervous system disorders and cancer.

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References

  1. Naldini L, Blomer U, Gage FH, Trono D, Verma IM . Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proc Natl Acad Sci USA 1996; 93: 11382–11388.

    Article  CAS  Google Scholar 

  2. Waehler R, Russell SJ, Curiel DT . Engineering targeted viral vectors for gene therapy. Nat Rev Genet 2007; 8: 573–587.

    Article  CAS  Google Scholar 

  3. Smith JS, Keller JR, Lohrey NC, McCauslin CS, Ortiz M, Cowan K et al. Redirected infection of directly biotinylated recombinant adenovirus vectors through cell surface receptors and antigens. Proc Natl Acad Sci USA 1999; 96: 8855–8860.

    Article  CAS  Google Scholar 

  4. Zhong Q, Kolls JK, Schwarzenberger P . Retrovirus molecular conjugates. A novel, high transduction efficiency, potentially safety-improved, gene transfer system. J Biol Chem 2001; 276: 24601–24607.

    Article  CAS  Google Scholar 

  5. Ponnazhagan S, Mahendra G, Kumar S, Thompson JA, Castillas M . Conjugate-based targeting of recombinant adeno-associated virus type 2 vectors by using avidin-linked ligands. J Virol 2002; 76: 12900–12907.

    Article  CAS  Google Scholar 

  6. Purow B, Staveley-O’Carroll K . Targeting of vaccinia virus using biotin-avidin viral coating and biotinylated antibodies. J Surg Res 2005; 123: 49–54.

    Article  CAS  Google Scholar 

  7. Parrott MB, Mok H, Campos SK, Adams KE, Mercier GT, Barry MA . Metabolically biotinylated adenovirus for cell targeting, ligand screening, and vector purification. Mol Ther 2003; 8: 688–700.

    Article  CAS  Google Scholar 

  8. Arnold GS, Sasser AK, Stachler MD, Bartlett JS . Metabolic biotinylation provides a unique platform for the purification and targeting of multiple AAV vector serotypes. Mol Ther 2006; 14: 97–106.

    Article  CAS  Google Scholar 

  9. Stachler MD, Bartlett JS . Mosaic vectors comprised of modified AAV1 capsid proteins for efficient vector purification and targeting to vascular endothelial cells. Gene Therapy 2006; 13: 926–931.

    Article  CAS  Google Scholar 

  10. Pereboeva L, Komarova S, Roth J, Ponnazhagan S, Curiel DT . Targeting EGFR with metabolically biotinylated fiber-mosaic adenovirus. Gene Therapy 2007; 14: 627–637.

    Article  CAS  Google Scholar 

  11. Raty JK, Airenne KJ, Marttila AT, Marjomaki V, Hytonen VP, Lehtolainen P et al. Enhanced gene delivery by avidin-displaying baculovirus. Mol Ther 2004; 9: 282–291.

    Article  CAS  Google Scholar 

  12. Schellingerhout D, Bogdanov A, Marecos E, Spear M, Breakefield X, Weissleder R . Mapping the in vivo distribution of herpes simplex virions. Hum Gene Ther 1998; 9: 1543–1549.

    Article  CAS  Google Scholar 

  13. Schellingerhout D, Rainov NG, Breakefield XO, Weissleder R . Quantitation of HSV mass distribution in a rodent brain tumor model. Gene Therapy 2000; 7: 1648–1655.

    Article  CAS  Google Scholar 

  14. Raty JK, Liimatainen T, Wirth T, Airenne KJ, Ihalainen TO, Huhtala T et al. Magnetic resonance imaging of viral particle biodistribution in vivo. Gene Therapy 2006; 13: 1440–1446.

    Article  CAS  Google Scholar 

  15. Raty JK, Liimatainen T, Huhtala T, Kaikkonen MU, Airenne KJ, Hakumaki JM et al. SPECT/CT imaging of baculovirus biodistribution in rat. Gene Therapy 2007; 14: 930–938.

    Article  CAS  Google Scholar 

  16. Morizono K, Xie Y, Ringpis GE, Johnson M, Nassanian H, Lee B et al. Lentiviral vector retargeting to P-glycoprotein on metastatic melanoma through intravenous injection. Nat Med 2005; 11: 346–352.

    Article  CAS  Google Scholar 

  17. Pariente N, Morizono K, Virk MS, Petrigliano FA, Reiter RE, Lieberman JR et al. A novel dual-targeted lentiviral vector leads to specific transduction of prostate cancer bone metastases in vivo after systemic administration. Mol Ther 2007; 15: 1973–1981.

    Article  CAS  Google Scholar 

  18. Kaikkonen MU, Raty JK, Airenne KJ, Wirth T, Heikura T, Yla-Herttuala S . Truncated vesicular stomatitis virus G protein improves baculovirus transduction efficiency in vitro and in vivo. Gene Therapy 2006; 13: 304–312.

    Article  CAS  Google Scholar 

  19. Recht L, Torres CO, Smith TW, Raso V, Griffin TW . Transferrin receptor in normal and neoplastic brain tissue: implications for brain-tumor immunotherapy. J Neurosurg 1990; 72: 941–945.

    Article  CAS  Google Scholar 

  20. Herbst RS . Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys 2004; 59: 21–26.

    Article  CAS  Google Scholar 

  21. Wojnicz D, Bar J, Jankowski S . The role of membrane glycoproteins CD46, CD55 and CD59 in protection of tumor cells against complement lysis. Postepy Hig Med Dosw 2002; 56: 603–616.

    CAS  PubMed  Google Scholar 

  22. Genove G, DeMarco U, Xu H, Goins WF, Ahrens ET . A new transgene reporter for in vivo magnetic resonance imaging. Nat Med 2005; 11: 450–454.

    Article  CAS  Google Scholar 

  23. Cohen B, Dafni H, Meir G, Harmelin A, Neeman M . Ferritin as an endogenous MRI reporter for noninvasive imaging of gene expression in C6 glioma tumors. Neoplasia 2005; 7: 109–117.

    Article  CAS  Google Scholar 

  24. Cohen B, Ziv K, Plaks V, Israely T, Kalchenko V, Harmelin A et al. MRI detection of transcriptional regulation of gene expression in transgenic mice. Nat Med 2007; 13: 498–503.

    Article  CAS  Google Scholar 

  25. Cronin J, Zhang XY, Reiser J . Altering the tropism of lentiviral vectors through pseudotyping. Curr Gene Ther 2005; 5: 387–398.

    Article  CAS  Google Scholar 

  26. 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: 8033–8037.

    Article  CAS  Google Scholar 

  27. Park F, Ohashi K, Kay MA . Therapeutic levels of human factor VIII and IX using HIV-1-based lentiviral vectors in mouse liver. Blood 2000; 96: 1173–1176.

    CAS  PubMed  Google Scholar 

  28. Watson DJ, Kobinger GP, Passini MA, Wilson JM, Wolfe JH . Targeted transduction patterns in the mouse brain by lentivirus vectors pseudotyped with VSV, Ebola, Mokola, LCMV, or MuLV envelope proteins. Mol Ther 2002; 5: 528–537.

    Article  CAS  Google Scholar 

  29. Kumar M, Bradow BP, Zimmerberg J . Large-scale production of pseudotyped lentiviral vectors using baculovirus GP64. Hum Gene Ther 2003; 14: 67–77.

    Article  CAS  Google Scholar 

  30. Schauber CA, Tuerk MJ, Pacheco CD, Escarpe PA, Veres G . Lentiviral vectors pseudotyped with baculovirus gp64 efficiently transduce mouse cells in vivo and show tropism restriction against hematopoietic cell types in vitro. Gene Therapy 2004; 11: 266–275.

    Article  CAS  Google Scholar 

  31. Kang Y, Xie L, Tran DT, Stein CS, Hickey M, Davidson BL et al. Persistent expression of factor VIII in vivo following nonprimate lentiviral gene transfer. Blood 2005; 106: 1552–1558.

    Article  CAS  Google Scholar 

  32. Sinn PL, Burnight ER, Hickey MA, Blissard GW, McCray Jr PB . Persistent gene expression in mouse nasal epithelia following feline immunodeficiency virus-based vector gene transfer. J Virol 2005; 79: 12818–12827.

    Article  CAS  Google Scholar 

  33. Green NM . Avidin and streptavidin. Methods Enzymol 1990; 184: 51–67.

    Article  CAS  Google Scholar 

  34. Livnah O, Bayer EA, Wilchek M, Sussman JL . Three-dimensional structures of avidin and the avidin-biotin complex. Proc Natl Acad Sci USA 1993; 90: 5076–5080.

    Article  CAS  Google Scholar 

  35. Pazy Y, Kulik T, Bayer EA, Wilchek M, Livnah O . Ligand exchange between proteins: exchange of biotin and biotin derivatives between avidin and streptavidin. J Biol Chem 2002; 277: 30892–30900.

    Article  CAS  Google Scholar 

  36. Lin AH, Kasahara N, Wu W, Stripecke R, Empig CL, Anderson WF et al. Receptor-specific targeting mediated by the coexpression of a targeted murine leukemia virus envelope protein and a binding-defective influenza hemagglutinin protein. Hum Gene Ther 2001; 12: 323–332.

    Article  CAS  Google Scholar 

  37. Morizono K, Bristol G, Xie YM, Kung SK, Chen IS . Antibody-directed targeting of retroviral vectors via cell surface antigens. J Virol 2001; 75: 8016–8020.

    Article  CAS  Google Scholar 

  38. Long G, Pan X, Kormelink R, Vlak JM . Functional entry of baculovirus into insect and mammalian cells is dependent on clathrin-mediated endocytosis. J Virol 2006; 80: 8830–8833.

    Article  CAS  Google Scholar 

  39. Matilainen H, Rinne J, Gilbert L, Marjomaki V, Reunanen H, Oker-Blom C . Baculovirus entry into human hepatoma cells. J Virol 2005; 79: 15452–15459.

    Article  CAS  Google Scholar 

  40. Funke S, Maisner A, Muhlebach MD, Koehl U, Grez M, Cattaneo R et al. Targeted cell entry of lentiviral vectors. Mol Ther 2008; 16: 1427–1436.

    Article  CAS  Google Scholar 

  41. Yang L, Bailey L, Baltimore D, Wang P . Targeting lentiviral vectors to specific cell types in vivo. Proc Natl Acad Sci USA 2006; 103: 11479–11484.

    Article  CAS  Google Scholar 

  42. Zhou J, Blissard GW . Identification of a GP64 subdomain involved in receptor binding by budded virions of the baculovirus Autographica californica multicapsid nucleopolyhedrovirus. J Virol 2008; 82: 4449–4460.

    Article  CAS  Google Scholar 

  43. Bradley Jr WG . Hemorrhage and hemorrhagic infections in the brain. Neuroimaging Clin N Am 1994; 4: 707–732.

    PubMed  Google Scholar 

  44. Sarkis C, Serguera C, Petres S, Buchet D, Ridet JL, Edelman L et al. Efficient transduction of neural cells in vitro and in vivo by a baculovirus-derived vector. Proc Natl Acad Sci USA 2000; 97: 14638–14643.

    Article  CAS  Google Scholar 

  45. Lehtolainen P, Tyynela K, Kannasto J, Airenne KJ, Yla-Herttuala S . Baculoviruses exhibit restricted cell type specificity in rat brain: a comparison of baculovirus- and adenovirus-mediated intracerebral gene transfer in vivo. Gene Therapy 2002; 9: 1693–1699.

    Article  CAS  Google Scholar 

  46. Follenzi A, Naldini L . Generation of HIV-1 derived lentiviral vectors. Methods Enzymol 2002; 346: 454–465.

    Article  CAS  Google Scholar 

  47. Lesch HP, Turpeinen S, Niskanen EA, Mahonen AJ, Airenne KJ, Yla-Herttuala S . Generation of lentivirus vectors using recombinant baculoviruses. Gene Therapy 2008; 15: 1280–1286.

    Article  CAS  Google Scholar 

  48. Sandmair AM, Turunen M, Tyynela K, Loimas S, Vainio P, Vanninen R et al. Herpes simplex virus thymidine kinase gene therapy in experimental rat BT4C glioma model: effect of the percentage of thymidine kinase-positive glioma cells on treatment effect, survival time, and tissue reactions. Cancer Gene Ther 2000; 7: 413–421.

    Article  CAS  Google Scholar 

  49. Cozzi A, Corsi B, Levi S, Santambrogio P, Albertini A, Arosio P . Overexpression of wild type and mutated human ferritin H-chain in HeLa cells: in vivo role of ferritin ferroxidase activity. J Biol Chem 2000; 275: 25122–25129.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Siiri Väistö, Juha Ruuskanen, Anne Martikainen, Katja Salminen, Joonas Malinen and Riikka Eisto for excellent technical assistance. We thank Ann-Marie Määttä and Haritha Samaranayake for their help with the animal work. We are grateful to Olli Laitinen for fruitful conversations during the course of the project. We thank Markku Kulomaa for providing streptavidin-encoding plasmid and anti-avidin antibody and Edward A Bayer and Meir Wilchek for the generous gift of anti-streptavidin. We also thank Paolo Arosio for the rHO2 antibody. This study was supported by Ark Therapeutics Group Plc., Finnish Academy, Finnish Foundation for Cardiovascular Research and Finnish Cultural Foundation, North Savo Regional fund.

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Correspondence to S Ylä-Herttuala.

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Kaikkonen, M., Lesch, H., Pikkarainen, J. et al. (Strept)avidin-displaying lentiviruses as versatile tools for targeting and dual imaging of gene delivery. Gene Ther 16, 894–904 (2009). https://doi.org/10.1038/gt.2009.47

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