T Lymphocyte Based HIV Gene Therapy Strategies

  • Tracy Gentry


Diseases of the immune system have been the primary focus of gene therapy strategies targeted to T lymphocytes. These diseases include adenosine deaminase deficiency (ADA), purine nucleoside phosphorylase deficiency (PNP),leukocyte adhesion deficiency (LAD), and chronic granulomatus disease (CGD).1 Other disease states have also become candidates for gene therapy approaches such as treatment of tumors through modification of tumor infiltrating lymphocytes.2,3 The treatment of viral diseases including HIV, EBV and CMV infection with gene modified T lymphocytes is another area of intense research 44–19,57 T cells are attractive target cells for gene therapy strategies because they are easy to obtain from the peripheral blood and are relatively easy to expand, select and characterize.1,21–23


Human Immunodeficiency Virus Gene Therapy Human Immunodeficiency Virus Type Epstein Barr Virus Human Immunodeficiency Virus Infection 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Cournoyer D. Gene therapy of the immune system. Annu Rev Immunology 1993; 11: 297–329.CrossRefGoogle Scholar
  2. 2.
    Nash M, Platsoucas C, Wong B, Wong P, Cottler-Fox M, Otto E, Freedman R. Transduction of rIL-2 expanded CD4+ and CD8+ ovarian TIL-derived T- cell lines with the GiNa (neoAR) replication-deficient retroviral vector. Human Gene Therapy 1995; 6: 1379–1389.PubMedCrossRefGoogle Scholar
  3. 3.
    Hwu P, Rosenberg S. The genetic modification of T cells for cancer therapy: an overview of laboratory and clinical trials. Cancer Detection and Prevention 1994; 18 (1): 43–50.PubMedGoogle Scholar
  4. 4.
    Woffendin C, Yang Z, Udaykumar R, Xu L, Yang N, Sheehy M, Nabel G. Nonviral and viral delivery of a human immunodeficiency virus protective gene into primary human T cells. Proc Natl Acad Sci USA 1994; 91: 11581–11585.PubMedCrossRefGoogle Scholar
  5. 5.
    Leavitt M, Yu M, Yamada O, Gunter K, Looney D, Poeschla E, Wong-Staal F. Transfer of an anti-HIV-1 ribozyme gene into primary human lymphocytes. Human Gene Therapy 1994; 51115–1120.Google Scholar
  6. 6.
    Sun LQ, Pyati J, Smythe J, Wang L, Macpherson J, Gerlach W, Symonds G. Resistance to human immunodeficiency virus type 1 infection conferred by transduction of human peripheral blood lymphocytes with ribozyme, antisense, or polymeric trans-activation response element constructs. Proc Natl Acad Sci USA 1995; 92: 7272–7276.PubMedCrossRefGoogle Scholar
  7. 7.
    Vandendriessche T, Chuah M, Chiang L, Chang L, Ensoli B, Morgan R. Inhibition of clinical human immunodeficiency virus (HIV) type 1 isolates in primary CD4+ T lymphocytes by retroviral vectors expressing anti-HIV genes. Virol 1995; 69 (7): 4045–4052.Google Scholar
  8. 8.
    Duan L, Zhu M, Bagasra O, Pomerantz R. Intracellular immunization against HIV-1 infection of human T lymphocytes: utility of anti-Rev single-chain variable fragments. Human Gene Therapy 1995; 6: 1561–1573.PubMedCrossRefGoogle Scholar
  9. 9.
    Yamada O, Yu M, Yee J, Kraus G, Looney D, Wong-Staal F. Intracellular immunization of human T cells with a hairpin ribozyme against human immunodeficiency virus type 1. Gene Therapy 1994; 1: 38–45.PubMedGoogle Scholar
  10. 10.
    Lori F, Lisziewicz J, Smythe J, Cara A, Bunnag T, Curiel D, Gallo R. Rapid protection against human immunodeficiency virus type 1 (HIV-1) replication mediated by high efficiency nonretroviral delivery of genes interfering with HIV-1 tat and gag. Gene Therapy 1994; 1: 27–31.PubMedGoogle Scholar
  11. 11.
    Pomerantz R, Trono D. Genetic therapies for HIV infections: promise for the future. AIDS 1995; 9: 985–993.PubMedCrossRefGoogle Scholar
  12. 12.
    Sullenger B, Gallardo H, Ungers G, Gilboa E. Overexpression of TAR sequences renders cells resistant to human immunodeficiency virus replication. Cell 1990; 63: 601–608.PubMedCrossRefGoogle Scholar
  13. 13.
    Lee S, Gallardo H, Gilboa E, Smith C. Inhibition of human immunodeficiency virus type 1 in human T cells by a potent Rev response element decoy consisting of the 13-nucleotide minimal Rev-binding domain. Virol 1994; 68 (12): 8254–8264.Google Scholar
  14. 14.
    Shaheen F, Duan L, Zhu M, Bagasra O, Pomerantz R. Targeting human immunodeficiency virus type 1 reverse transcriptase by intracellular expression of single chain variable fragments to inhibit early stages of the viral life cycle. Virol 1996; 70 (6): 3392–3400.Google Scholar
  15. 15.
    Miele G, Lever A. Expression of mutant and wild-type gag proteins for gene therapy in HIV-1 infection. Gene Therapy 1996; 3: 357–361.PubMedGoogle Scholar
  16. 16.
    Plavec I et al. High transdominant RevMio protein levels are required to inhibit HIV-1 replication in cell lines and primary T cells: implication for gene therapy of AIDS. Gene Therapy 1997; 4: 128–139.PubMedCrossRefGoogle Scholar
  17. 17.
    Lisziewicz J, Sun D, Lisziewicz A, Gallo R. Antitat gene therapy: a candidate for late-stage AIDS patients. Gene Therapy 1995; 2: 218–222.PubMedGoogle Scholar
  18. 18.
    Caputo A et al. Inhibition of HIV-1 replication and reactivation from latency by tat transdominant negative mutants in the cysteine rich region. Gene Therapy 1996; 3: 235–245.PubMedGoogle Scholar
  19. 19.
    Culver K et al. Lymphocytes as cellular vehicles for gene therapy in mouse and man. Proc Natl Acad Sci USA 1991; 883155–3159.Google Scholar
  20. 20.
    Blaese R et al. T lymphocyte-directed gene therapy for ADA-SCID: Initial trial results after 4 years. Science 1995; 270: 475–480.PubMedCrossRefGoogle Scholar
  21. 21.
    Rudoll T et al. High-efficiency retroviral vector mediated gene transfer into human peripheral blood CD4+ t lymphocytes. Gene Therapy 1996; 3: 695–705.PubMedGoogle Scholar
  22. 22.
    Miller D. Human gene therapy comes of age. Nature 1992; 357: 455–460.PubMedCrossRefGoogle Scholar
  23. 23.
    Blaese R. Progress toward gene therapy. Clinical Immunology and Immunopathology 1991; 61: 547–555.CrossRefGoogle Scholar
  24. 24.
    Flotte T, Carter B. Adeno-associated virus vectors for gene therapy. Gene Therapy 1995; 2357–362.Google Scholar
  25. 25.
    Muro-Cacho C, Samulski R, Kaplan D. Gene transfer in human lymphocytes using a vector based on adeno-associated viruses. Journal of Immunotherapy 1992; 11: 231–237.PubMedCrossRefGoogle Scholar
  26. 26.
    Chatterjee S, Johnson P, Wong K. Dual-target inhibition of HIV-1 in vitro by means of an adeno-associated virus antisense vector. Science 1992; 258: 1485–1488.PubMedCrossRefGoogle Scholar
  27. 27.
    Smith C et al. Transient protection of human T cells from human immunodefiency virus type 1 infection by transduction with adenoassociated viral vectors which express RNA decoys. Antiviral Research 1996; 3299–115.Google Scholar
  28. 28.
    Kass-Eisler A, Falck-Pedersen E, Elfenbein D, Alvira M, Buttrick P, Leinwand L. The impact of developmental stage, route of administration and the immune system on adenovirus-mediated gene tranfer. Gene Therapy 1994; 1395–402.Google Scholar
  29. 29.
    DeMatteo R et al. Gene transfer to the thymus: a means of abrogating the immune response to recombinant adenovirus. Annals of Surgery 1995; 222 (3): 229–242.PubMedCrossRefGoogle Scholar
  30. 30.
    Abe J et al. In vivo antitumor effect of cytotoxic T lymphocytes engineered to produce interferon-ip by adenovirus-mediated genetic transduction. Biochemical and Biophysical Research Communications 1996; 218 (oo29): 164–170.PubMedCrossRefGoogle Scholar
  31. 31.
    Nakamura Y et al. Adoptive immunotherapy with murine tumor-specific T lymphocytes engineered to secrete interleukin 2. Cancer Research 1994; 54, 5757–5760.PubMedGoogle Scholar
  32. 32.
    Philip R et al. Efficient and sustained gene expression in primary T lymphocytes, and primary and cultured tumor cells mediated by adeno-associated viral plasmid complexed to cationic liposomes. Molecular and Cellular Biology 1994; 14 (4): 2411–2418.PubMedCrossRefGoogle Scholar
  33. 33.
    Merwin J et al. CD5-mediated specific delivery of DNA to T lymphocytes: Compartmentalization augmented by adenovirus Immunol Meth 1995; 186: 257–266.Google Scholar
  34. 34.
    Kelleher Z, Vos J. Long-term episomal gene delivery in human lymphoid cells using human and avian adenoviral-assisted transfection. BioTechniques 1994; 17 (6): u10 - u17.Google Scholar
  35. 35.
    Buschle M et al. Receptor-mediated gene transfer into human T lymphocytes via binding of DNA/CD3 antibody particles to the CD3 T cell receptor complex. Human Gene Therapy 1995; 6: 753–761.PubMedCrossRefGoogle Scholar
  36. 36.
    Burkholder J, Decker J, Yang N. Rapid transgene expression in lymphocyte and macrophage primary cultures after particle bombardment-mediated gene transfer. Immunol Meth 1993; 165: 149–156.CrossRefGoogle Scholar
  37. 37.
    Hui K, Sabapathy T, Oei A, Chia T. Generation of allo-reactive cytotoxic T lymphocytes by particle bombardment-mediated gene transfer. Journal of Immunological Methods 1994; 171147–155.Google Scholar
  38. 38.
    Strair R, Towle M, Heald P, Smith B. Retroviral mediated transfer and expression of exogenous genes in primary lymphoid cells: Assaying for a viral transactivator activity in normal and malignant cells. Blood 199o; 76(6):1201–1208.Google Scholar
  39. 39.
    Mavilio F et al. Peripheral blood lymphocytes as target cells of retroviral vector-mediated gene transfer. Blood 1994; 83 (7): 1988–1997.PubMedGoogle Scholar
  40. 40.
    Hanenberg H, Xiao X, Dilloo D, Hashino K, Kato I, Williams D. Colocalization of retrovirus and target cells on specific fibronectin fragments increases genetic transduction of mammalian cells. Nature Medicine 1996; 2 (8): 876–882.PubMedCrossRefGoogle Scholar
  41. 41.
    Conneally E, Bardy P, Eaves CJ, Thomas T, Chappel S, Shpall EJ, Humphries RK. Rapid and efficient selection of human hematopoietic cells expressing murine heat-stable antigen as an indicator of retroviral-mediated gene transfer. Blood 1996; 874, 56–64.Google Scholar
  42. 42.
    Medin JA et al. A bicistronic therapeutic retroviral vector enables sorting of transduced CD34+ cells and corrects the enzyme deficiency in cells from Gaucher patients. Blood 1996; 87: 17, 54–62.Google Scholar
  43. 43.
    Planelles V, Haislip A, Withers-Ward ES, Stewart SA, Xie Y, Shah NP, Chen ISY. A new reporter system for detection of retroviral infection. Gene Therapy 1995; 2, 369–376.PubMedGoogle Scholar
  44. 44.
    McCowage GB, Phillips KL, Gentry TL, Hull S, Kurtzberg J, Gilboa E, Smith C. Multiparameter FACS analysis of retroviral vector gene transfer into primitive umbilical cord blood cells. Experimental Hematology 1998; 26: 288–298.PubMedGoogle Scholar
  45. 45.
    Phillips K, Gentry T, McCowage G, Gilboa E, Smith C. Cell-surface markers for assessing gene transfer into human hematopoietic cells. Nature Medicine 1996; 2 (10): 1154–1156.PubMedCrossRefGoogle Scholar
  46. 46.
    Pawliuk R, Kay R, Lansdorp P, Humphries RK. Selection of retrovirally transduced hematopoietic cells using CD24 as a marker of gene transfer. Blood 1994; 84: 28, 68–77.Google Scholar
  47. 47.
    Kotani H et al. Improved methods of retroviral vector transduction and production for gene therapy. Human Gene Therapy 1994; 5: 19–28.PubMedCrossRefGoogle Scholar
  48. 48.
    Bunnell BA, Muul LM, Donahue RE, Blaese RM, Morgan RA. High-efficiency retroviral-mediated gene transfer into human and nonhuman primate peripheral blood lymphocytes. Proc Natl Acad Sci 1995; 92: 7739–7743.PubMedCrossRefGoogle Scholar
  49. 49.
    Hodgson C, Solaiman F. Virosomes: Cationic liposomes enhance retroviral transduction. Nature Biotechnology 1996; 14: 339–342.PubMedCrossRefGoogle Scholar
  50. 50.
    Morling F, Russel S. Enhanced transduction efficiency of retroviral vectors coprecipitated with calcium phosphate. Gene Therapy 1995; 2: 504–508.PubMedGoogle Scholar
  51. 51.
    Chuck A, Palsson B. Consistent and high rates of gene transfer can be obtained using flow-through transduction over a wide range of retrovial titers. Human Gene Therapy 1996; 7: 743–750.PubMedCrossRefGoogle Scholar
  52. 52.
    Bordignon C et al. Gene therapy in peripheral blood lymphocytes and bone marrow for ADA-immunodeficient patients. Science 1995; 270: 470–475.PubMedCrossRefGoogle Scholar
  53. 53.
    Heslop HE et al. Administration of neomycin-resistance-genemarked EBV-specific cytotoxic T lymphocytes to recipients of mismatched-related or phenotypically similar unrelated donor marrow grafts. Human Gene Therapy 1994; 5: 381–97.PubMedCrossRefGoogle Scholar
  54. 54.
    Heslop HE et al. Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nature Medicine 1996; 2: 551–5.PubMedCrossRefGoogle Scholar
  55. 55.
    Rooney CM et al. Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet 1995; 345: 9–13.PubMedCrossRefGoogle Scholar
  56. 56.
    Riddell SR et al. T cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients [see comments]. Nature Medicine 1996; 2: 216–23.PubMedCrossRefGoogle Scholar
  57. 57.
    Woffendin C, Ranga U, Yang Z, Xu L, Nabel G. Expression of a protective gene prolongs survival of T cells in human immunodeficiency virus-infected patients. Proc Natl Acad Sci USA 1996; 93: 2889–2894.PubMedCrossRefGoogle Scholar
  58. 58.
    Finer M, Dull T, Qin L, Farson D, Roberts M. kat: A high efficiency retroviral transduction sytstem for primary human T lymphocytes. Blood 1994; 83 (1): 43–50.PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • Tracy Gentry

There are no affiliations available

Personalised recommendations