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Gene Therapy

A gene therapy model for retrovirus-induced disease with a viral env gene: expression-dependent resistance in immunosuppressed hosts

Leukemia volume 15, pages 1779–1784 (2001)Cite this article

Abstract

At the initial stage of retroviral infection, virion envelope glycoprotein (env product) binds to cell surface receptors. Cells infected with retrovirus or into which the env gene was introduced, become resistant to superinfection by other retroviruses with the same receptor specificity, a phenomenon known as receptor interference. We have demonstrated previously that the introduction of an env gene from a truncated endogenous ecotropic murine leukemia virus (MuLV), the Fv-4 resistance (Fv-4r) gene, into the bone marrow hematopoietic cells of Fv-4 sensitive (Fv-4s) mice protected mice from ecotropic retrovirus-induced disease. Using the gene transfer system under the control of the retroviral vector and bone marrow transplantation (BMT), here we could show that the expression of an introduced Fv-4r gene in hematopoietic cells continued for more than 1 year after BMT. To determine the inhibitory mechanism of Fv-4r env gene expression against FLV-infection in this model system, peripheral blood mononuclear cells (PBMCs), or spleen cells from chimeras with various degrees of env-expression, were mixed with green fluorescence protein (GFP)-conjugated Friend MuLV env glycoprotein (GFP-Fr-ENV). The amount of GFP-Fr-ENV bound to these cells inversely correlated with the expression intensity of the transduced env gene indicating the receptor interference effect. Next, to see whether transduction of the Fv-4r gene would protect an immunosuppressed host from FLV-induced leukemogenesis, we generated immunocompromised chimeras by transplanting env-transduced bone marrow cells into a thymectomized host. These chimeras also resisted FLV-induced leukemogenesis, indicating that receptor interference-based gene therapy could become a therapeutic basis for immunodeficiency virus-induced diseases in vivo.

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References

  1. Fauci AS . The AIDS epidemic: considerations for the 21st century New Engl J Med 1999 341: 1046–1050

    Article  CAS  Google Scholar 

  2. Battegay M, Harr T, Sponagel L . Salvage treatment against human immunodeficiency virus Ann Med 1999 31: 253–260

    Article  CAS  Google Scholar 

  3. Finzi D, Blankson J, Siliciano JD, Margolick JB, Chandwick K, Pierson T, Smith K, Lisziewicz J, Lori F, Flexner C, Quinn TC, Chaisson RE, Rosenberg E, Walker B, Gange S, Gallant J, Siliciano RF . Latent infection of CD4+ T-cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy Nature Med 1999 5: 512–517

    Article  CAS  Google Scholar 

  4. Deng X, Ueda H, Su SB, Gong W, Dunlop NM, Gao JL, Murphy PM, Wang JM . A synthetic peptide derived from human immunodeficiency virus type 1 gp 120 downregulates the expression and function of chemokine receptors CCR5 and CXCR4 in monocytes by activating the 7-transmembrane G-protein-coupled receptor FPRL1/LXA4R Blood 1999 94: 1165–1173

    CAS  PubMed  Google Scholar 

  5. Kalinkovich A, Weisman Z, Bentwich Z . Chemokines and chemokine receptors: role in HIV infection Immunol Lett 1999 68: 281–287

    Article  CAS  Google Scholar 

  6. Schwarz MK, Wells TN . Interfering with chemokine networks – the hope for new therapeutics Curr Opin Chem Biol 1999 3: 407–417

    Article  CAS  Google Scholar 

  7. Michael NL, Moore JP . HIV-1 entry inhibitors: evading the issue Nature Med 1999 5: 740–742

    Article  CAS  Google Scholar 

  8. Donzella GA, Schols D, Lin SW, Este JA, Nagashima KA, Maddon PJ, Allaway GP, Sakmar TP, Henson G, De Clercq E, Moore JP . AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor Nature Med 1998 4: 72–77

    Article  CAS  Google Scholar 

  9. Baba M, Nishimura O, Kanzaki N, Okamoto M, Sawada H, Iizawa Y, Shiraishi M, Aramaki Y, Okonogi K, Ogawa Y, Meguro K, Fujino M . A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity Proc Natl Acad Sci USA 1999 96: 5698–5703

    Article  CAS  Google Scholar 

  10. Chan DC, Kim PS . HIV entry and its inhibition Cell 1998 93: 681–684

    Article  CAS  Google Scholar 

  11. Eckert DM, Malashkevich VN, Hong LH, Carr PA, Kim PS . Inhibiting HIV entry: discovery of D-peptide inhibitors that target the gp41 coiled coil pocket Cell 1999 99: 103–115

    Article  CAS  Google Scholar 

  12. Kitagawa M, Aizawa S, Kamisaku H, Hirokawa K, Ikeda H . Protection of retrovirus-induced disease by transplantation of bone marrow cells transduced with MuLV env gene via retrovirus vector Exp Hematol 1999 27: 234–241

    Article  CAS  Google Scholar 

  13. Ikeda H, Laigret F, Martin MA, Rapske R . Characterization of a molecularly cloned retroviral sequence associated with Fv-4 resistance J Virol 1985 55: 768–777

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Masuda M, Yoshikura H . Construction and characterization of the recombinant Moloney murine leukemia viruses bearing the mouse Fv-4 env gene J Virol 1990 64: 1033–1043

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ikeda H, Sugimura H . Fv-4 resistance gene: a truncated endogenous murine leukemia virus with ecotropic interference properties J Virol 1989 63: 5405–5413

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Matano T, Odawara T, Ohshima M, Yoshikura H, Iwamoto A . Trans-dominant interference with virus infection at two different stages by a mutant envelope protein of Friend murine leukemia virus J Virol 1993 67: 2026–2033

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kitagawa M, Aizawa S, Kamisaku H, Ikeda H, Hirokawa K, Sado T . Cell-free transmission of Fv-4 resistance gene product controlling Friend leukemia virus-induced leukemogenesis: a unique mechanism for interference with viral infection Blood 1995 86: 1557–1563

    CAS  PubMed  Google Scholar 

  18. Ikeda H, Kato K, Suzuki T, Kitani H, Matsubara Y, Takase-Yoden, S, Watanabe R, Kitagawa M, Aizawa S . Properties of the naturally occurring soluble surface glycoprotein of ecotropic murine leukemia virus: binding specificity and possible conformational change after binding to receptor J Virol 2000 74: 1815–1826

    Article  CAS  Google Scholar 

  19. Nihrane A, Lebedeva I, Lyu MS, Fujita K, Silver J . Secretion of a murine retroviral Env associated with resistance to infection J Gen Virol 1997 78: 785–793

    Article  CAS  Google Scholar 

  20. Nihrane A, Fujita K, Willey R, Lyu MS, Silver J . Murine leukemia virus envelope protein in transgenic-mouse serum blocks infection in vitro J Virol 1998 72: 8462

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Limjoco TI, Dickie P, Ikeda H, Silver J . Transgenic Fv-4 mice resistant to Friend virus J Virol 1993 67: 4163–4168

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Nihrane A, Silver J . Spontaneous priming for anti-viral envelope cytotoxic T lymphocytes in mice transgenic for a murine leukaemia virus envelope gene (Fv-4) Immunology 1997 90: 219–228

    Article  CAS  Google Scholar 

  23. Higo K, Kubo Y, Iwatani Y, Ono T, Maeda M, Hiai H, Masuda T, Kuribayashi K, Zhang F, Lamin TY, Adachi A, Ishimoto A . Susceptibility of nude mice carrying the Fv-4 gene to Friend murine leukemia virus infection J Virol 1997 71: 750–754

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang F, Ya TL, Iwatani Y, Higo K, Suzuki Y, Tanaka M, Nakahara T, Ono T, Sakai H, Kuribayashi K, Ishimoto A . Resistance to Friend murine virus infection conferred by the Fv-4 gene is recessive but appears dominant from the effect of the immune system J Virol 2000 74: 6193–6197

    Article  CAS  Google Scholar 

  25. Kuriu A, Fujita J, Kanakura Y, Yonezawa T, Yoshida K, Kitamura Y . Acceleration of a murine T-cell leukemia associated with loss of interleukin-3 producing activity Leuk Res 1989 13: 77–82

    Article  CAS  Google Scholar 

  26. Kitagawa M, Kamisaku H, Sado T, Kasuga T . Friend leukemia virus-induced leukemogenesis in fully H-2 incompatible C57BL/6→C3H radiation bone marrow chimeras Leukemia 1993 7: 1041–1046

    CAS  PubMed  Google Scholar 

  27. Kitagawa M, Kamisaku H, Aizawa S, Sado T . Bone marrow transplantation from Fv-4-resistant donors rescues Friend leukemia virus-infected mice from leukemia: a model of bone marrow transplantation therapy against retroviral infection Leukemia 1994 8: 2200–2206

    CAS  PubMed  Google Scholar 

  28. Sado T, Kamisaku H, Kubo E . Strain difference in the radio-sensitivity of immunocompetent cells and its influence on the residual host-versus-graft rejection in lethally irradiated mice grafted with semiallogeneic bone marrow J Immunol 1985 134: 704–710

    CAS  PubMed  Google Scholar 

  29. Rowe WP, Pugh WE, Hartley JW . Plaque assay techniques for murine leukemia viruses Virology 1970 42: 1136–1139

    Article  CAS  Google Scholar 

  30. Koch W, Hunsmann G, Friedrich R . Nucleotide sequence of the envelope gene of Friend murine leukemia virus J Virol 1983 45: 1–9

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Suzuki T, Aizawa S, Ikeda H . Expression of receptor for ecotropic murine leukemia virus on hematopoietic cells Arch Virol 2001 146: 507–519

    Article  CAS  Google Scholar 

  32. Matsuura Y, Possee RD, Overton HA, Bishop DH . Baculovirus expression vectors: the requirements for high level expression of proteins, including glycoproteins J Gen Virol 1987 68: 1233–1250

    Article  CAS  Google Scholar 

  33. Possee RD, Howard SC . Analysis of the polyhedrin gene promotor of the Autographa californica nuclear polyhedrosis virus Nucleic Acids Res 1987 15: 10233–10248

    Article  CAS  Google Scholar 

  34. Duprez V, Maziarz R, Weinberger O, Burakoff SJ . Thymectomized, irradiated, and bone marrow-reconstituted chimeras have normal cytolytic T lymphocyte precursors but a defect in lymphokine production J Immunol 1984 132: 2185–2189

    CAS  PubMed  Google Scholar 

  35. Lyu MS, Nihrane A, Kozak CA . Receptor-mediated interference mechanism responsible for resistance to polytropic leukemia viruses in Mus castaneus J Virol 1999 73: 3733–3736

    CAS  PubMed  Google Scholar 

  36. Feng Y, Broder CC, Kennedy PE, Berger EA . HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G-protein-coupled receptor Science 1996 272: 872–877

    Article  CAS  Google Scholar 

  37. Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, Murphy PM, Berger EA . CC CKR5: a RANTES, MIP-1a, MIP-1b receptor as a fusion cofactor for macrophage-tropic HIV-1 Science 1996 272: 1955–1958

    Article  CAS  Google Scholar 

  38. Battini JL, Danos O, Heard JM . Receptor-binding domain of murine leukemia virus envelope glycoproteins J Virol 1995 69: 713–719

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Durant J, Clevenbergh P, Halfon P, Delgiudice P, Porsin S, Simonet P, Montagne N, Boucher CA, Schapiro JM, Dellamonica P . Drug-resistant genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial Lancet 1999 353: 2195–2199

    Article  CAS  Google Scholar 

  40. Kilby JM, Hopkins S, Venetta TM, DiMassimo B, Cloud GA, Lee JY, Alldredge L, Hunter E, Lambert D, Bolognesi D, Matthews T, Johnson MR, Nowak MA, Shaw GM, Saag MS . Potent suppression of HIV-1 replications in humans by T-20, a peptide inhibitor of gp41-mediated virus entry Nature Med 1998 4: 1302–1307

    Article  CAS  Google Scholar 

  41. Auchincloss H, Sachs DH . Mechanisms of tolerance in murine radiation bone marrow chimeras. I. Non-specific suppression of alloreactivity by spleen cells from early, but not late, chimeras Transplantation 1983 36: 436–441

    Article  Google Scholar 

  42. Sprent J, Kosaka H, Gao EK . T cell tolerance after bone marrow transplantation in mice Bone Marrow Transplant 1992 10 (Suppl.): 1–5

    Google Scholar 

Download references

Acknowledgements

This work was supported by Special Project Research Grants from the Science and Technology Agency and by a grant-in-aid for Scientific Research from the Ministry of Education, Science and Culture of Japan.

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Authors and Affiliations

  1. Department of Pathology and Immunology, Aging and Developmental Sciences, Tokyo Medical and Dental University, Graduate School, Tokyo, Japan

    M Kitagawa, S Yamaguchi & K Hirokawa

  2. Radiation Hazards Research Group, National Institute of Radiological Sciences, Anagawa, Chiba, Japan

    S Aizawa & T Sado

  3. Laboratory of Virological Products, National Institute of Animal Health, Tsukuba, Ibaraki, Japan

    T Suzuki & H Ikeda

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  1. M Kitagawa
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Kitagawa, M., Aizawa, S., Sado, T. et al. A gene therapy model for retrovirus-induced disease with a viral env gene: expression-dependent resistance in immunosuppressed hosts. Leukemia 15, 1779–1784 (2001). https://doi.org/10.1038/sj.leu.2402279

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