Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Development of a nonintegrating Rev-dependent lentiviral vector carrying diphtheria toxin A chain and human TRAF6 to target HIV reservoirs

Gene Therapy volume 17, pages 1063–1076 (2010)Cite this article

Subjects

Abstract

Persistence of human immunodeficiency virus (HIV) despite highly active antiretroviral therapy (HAART) is a lasting challenge to virus eradication. To develop a strategy complementary to HAART, we constructed a series of Rev-dependent lentiviral vectors carrying diphtheria toxin A chain (DT-A) and its attenuated mutants, as well as human tumor necrosis factor receptor-associated factor 6 (TRAF6). Expression of these suicide genes following delivery through viral particles is dependent on Rev, which exists only in infected cells. Among these toxins, DT-A has been known to trigger cell death with as little as a single molecule, whereas two of the attenuated mutants in this study, DT-A(176) and DT-A(ΔN), were well tolerated by cells at low levels. TRAF6 induced apoptosis only with persistent overexpression. Thus, these suicide genes, which induce cell death at different expression levels, offer a balance between efficacy and safety. To minimize possible mutagenesis introduced by retroviral integration in nontarget cells, we further developed a nonintegrating Rev-dependent (NIRD) lentiviral vector to deliver these genes. In addition, we constructed a DT-A-resistant human cell line by introducing a human elongation factor 2 mutant into HEK293T cells. This allowed us to manufacture the first high-titer NIRD lentiviral particles carrying DT-A to target HIV-positive cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Torres RA, Barr M . Impact of combination therapy for HIV infection on inpatient census. N Engl J Med 1997; 336: 1531–1532.

    Article  CAS  PubMed  Google Scholar 

  2. Ramratnam B, Mittler JE, Zhang L, Boden D, Hurley A, Fang F et al. The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy. Nat Med 2000; 6: 82–85.

    Article  CAS  PubMed  Google Scholar 

  3. Zhu T, Muthui D, Holte S, Nickle D, Feng F, Brodie S et al. Evidence for human immunodeficiency virus type 1 replication in vivo in CD14(+) monocytes and its potential role as a source of virus in patients on highly active antiretroviral therapy. J Virol 2002; 76: 707–716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sedaghat AR, Siliciano JD, Brennan TP, Wilke CO, Siliciano RF . Limits on replenishment of the resting CD4+ T cell reservoir for HIV in patients on HAART. PLoS Pathog 2007; 3: e122.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Dybul M, Daucher M, Jensen MA, Hallahan CW, Chun TW, Belson M et al. Genetic characterization of rebounding human immunodeficiency virus type 1 in plasma during multiple interruptions of highly active antiretroviral therapy. J Virol 2003; 77: 3229–3237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy [see comments]. Science 1997; 278: 1295–1300.

    Article  CAS  PubMed  Google Scholar 

  7. Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci USA 1997; 94: 13193–13197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC, Spina CA et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia (see comments). Science 1997; 278: 1291–1295.

    Article  CAS  PubMed  Google Scholar 

  9. Furtado MR, Callaway DS, Phair JP, Kunstman KJ, Stanton JL, Macken CA et al. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. N Engl J Med 1999; 340: 1614–1622.

    Article  CAS  PubMed  Google Scholar 

  10. Lambotte O, Taoufik Y, de Goer MG, Wallon C, Goujard C, Delfraissy JF . Detection of infectious HIV in circulating monocytes from patients on prolonged highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2000; 23: 114–119.

    Article  CAS  PubMed  Google Scholar 

  11. Crowe SM, Sonza S . HIV-1 can be recovered from a variety of cells including peripheral blood monocytes of patients receiving highly active antiretroviral therapy: a further obstacle to eradication. J Leukoc Biol 2000; 68: 345–350.

    CAS  PubMed  Google Scholar 

  12. Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 1999; 5: 512–517.

    Article  CAS  PubMed  Google Scholar 

  13. Koenig S, Gendelman HE, Orenstein JM, Dal Canto MC, Pezeshkpour GH, Yungbluth M et al. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 1986; 233: 1089–1093.

    Article  CAS  PubMed  Google Scholar 

  14. Ramratnam B, Ribeiro R, He T, Chung C, Simon V, Vanderhoeven J et al. Intensification of antiretroviral therapy accelerates the decay of the HIV-1 latent reservoir and decreases, but does not eliminate, ongoing virus replication. J Acquir Immune Defic Syndr 2004; 35: 33–37.

    Article  PubMed  Google Scholar 

  15. Sonza S, Mutimer HP, Oelrichs R, Jardine D, Harvey K, Dunne A et al. Monocytes harbour replication-competent, non-latent HIV-1 in patients on highly active antiretroviral therapy. AIDS 2001; 15: 17–22.

    Article  CAS  PubMed  Google Scholar 

  16. Igarashi T, Brown CR, Endo Y, Buckler-White A, Plishka R, Bischofberger N et al. Macrophage are the principal reservoir and sustain high virus loads in rhesus macaques after the depletion of CD4+ T cells by a highly pathogenic simian immunodeficiency virus/HIV type 1 chimera (SHIV): implications for HIV-1 infections of humans. Proc Natl Acad Sci USA 2001; 98: 658–663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med 2009; 15: 893–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Aquaro S, Calio R, Balestra E, Bagnarelli P, Cenci A, Bertoli A et al. Clinical implications of HIV dynamics and drug resistance in macrophages. J Biol Regul Homeost Agents 1998; 12: 23–27.

    CAS  PubMed  Google Scholar 

  19. Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997; 277: 112–116.

    Article  CAS  PubMed  Google Scholar 

  20. Perelson AS, Essunger P, Cao Y, Vesanen M, Hurley A, Saksela K et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 1997; 387: 188–191.

    Article  CAS  PubMed  Google Scholar 

  21. Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, Pomerantz RJ . The challenge of finding a cure for HIV infection. Science 2009; 323: 1304–1307.

    Article  CAS  PubMed  Google Scholar 

  22. Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 1997; 278: 1447–1450.

    Article  CAS  PubMed  Google Scholar 

  23. Hatano H, Vogel S, Yoder C, Metcalf JA, Dewar R, Davey Jr RT et al. Pre-HAART HIV burden approximates post-HAART viral levels following interruption of therapy in patients with sustained viral suppression. AIDS 2000; 14: 1357–1363.

    Article  CAS  PubMed  Google Scholar 

  24. Davey Jr RT, Bhat N, Yoder C, Chun TW, Metcalf JA, Dewar R et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci USA 1999; 96: 15109–15114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Young J, Tang Z, Yu Q, Yu D, Wu Y . Selective killing of HIV-1-positive macrophages and T Cells by the Rev-dependent lentivirus carrying anthrolysin O from Bacillus anthracis. Retrovirology 2008; 5: 36.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Shannon JG, Ross CL, Koehler TM, Rest RF . Characterization of anthrolysin O, the Bacillus anthracis cholesterol-dependent cytolysin. Infect Immun 2003; 71: 3183–3189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. King W, Patel MD, Lobel LI, Goff SP, Nguyen-Huu MC . Insertion mutagenesis of embryonal carcinoma cells by retroviruses. Science 1985; 228: 554–558.

    Article  CAS  PubMed  Google Scholar 

  28. Li Z, Dullmann J, Schiedlmeier B, Schmidt M, von Kalle C, Meyer J et al. Murine leukemia induced by retroviral gene marking. Science 2002; 296: 497.

    Article  CAS  PubMed  Google Scholar 

  29. Greenfield L, Bjorn MJ, Horn G, Fong D, Buck GA, Collier RJ et al. Nucleotide sequence of the structural gene for diphtheria toxin carried by corynebacteriophage beta. Proc Natl Acad Sci USA 1983; 80: 6853–6857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kochi SK, Collier RJ . DNA fragmentation and cytolysis in U937 cells treated with diphtheria toxin or other inhibitors of protein synthesis. Exp Cell Res 1993; 208: 296–302.

    Article  CAS  PubMed  Google Scholar 

  31. Yamaizumi M, Mekada E, Uchida T, Okada Y . One molecule of diphtheria toxin fragment A introduced into a cell can kill the cell. Cell 1978; 15: 245–250.

    Article  CAS  PubMed  Google Scholar 

  32. Kunitomi M, Takayama E, Suzuki S, Yasuda T, Tsutsui K, Nagaike K et al. Selective inhibition of hepatoma cells using diphtheria toxin A under the control of the promoter/enhancer region of the human alpha-fetoprotein gene. Jpn J Cancer Res 2000; 91: 343–350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kelley VE, Bacha P, Pankewycz O, Nichols JC, Murphy JR, Strom TB . Interleukin 2-diphtheria toxin fusion protein can abolish cell-mediated immunity in vivo. Proc Natl Acad Sci USA 1988; 85: 3980–3984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Arora N, Masood R, Zheng T, Cai J, Smith DL, Gill PS . Vascular endothelial growth factor chimeric toxin is highly active against endothelial cells. Cancer Res 1999; 59: 183–188.

    CAS  PubMed  Google Scholar 

  35. Kuzel TM, Rosen ST, Gordon LI, Winter J, Samuelson E, Kaul K et al. Phase I trial of the diphtheria toxin/interleukin-2 fusion protein DAB486IL-2: efficacy in mycosis fungoides and other non-Hodgkin's lymphomas. Leuk Lymphoma 1993; 11: 369–377.

    Article  CAS  PubMed  Google Scholar 

  36. Frankel AE, Powell BL, Hall PD, Case LD, Kreitman RJ . Phase I trial of a novel diphtheria toxin/granulocyte macrophage colony-stimulating factor fusion protein (DT388GMCSF) for refractory or relapsed acute myeloid leukemia. Clin Cancer Res 2002; 8: 1004–1013.

    CAS  PubMed  Google Scholar 

  37. Frankel AE, Surendranathan A, Black JH, White A, Ganjoo K, Cripe LD . Phase II clinical studies of denileukin diftitox diphtheria toxin fusion protein in patients with previously treated chronic lymphocytic leukemia. Cancer 2006; 106: 2158–2164.

    Article  CAS  PubMed  Google Scholar 

  38. Li Y, McCadden J, Ferrer F, Kruszewski M, Carducci M, Simons J et al. Prostate-specific expression of the diphtheria toxin A chain (DT-A): studies of inducibility and specificity of expression of prostate-specific antigen promoter-driven DT-A adenoviral-mediated gene transfer. Cancer Res 2002; 62: 2576–2582.

    CAS  PubMed  Google Scholar 

  39. He L, Wu X, Siegel R, Lipsky PE . TRAF6 regulates cell fate decisions by inducing caspase 8-dependent apoptosis and the activation of NF-kappa B. J Biol Chem 2006; 281: 11235–11249.

    Article  CAS  PubMed  Google Scholar 

  40. Engelman A, Englund G, Orenstein JM, Martin MA, Craigie R . Multiple effects of mutations in human immunodeficiency virus type 1 integrase on viral replication. J Virol 1995; 69: 2729–2736.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Wu Y, Marsh JW . Selective transcription and modulation of resting T cell activity by preintegrated HIV DNA. Science 2001; 293: 1503–1506.

    Article  CAS  PubMed  Google Scholar 

  42. Wu Y, Marsh JW . Early transcription from nonintegrated DNA in human immunodeficiency virus infection. J Virol 2003; 77: 10376–10382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kelly J, Beddall MH, Yu D, Iyer SR, Marsh JW, Wu Y . Human macrophages support persistent transcription from unintegrated HIV-1 DNA. Virology 2008; 372: 300–312.

    Article  CAS  PubMed  Google Scholar 

  44. Iyer S, Yu D, Biancotto A, Margolis L, Wu Y . Measurement of HIV-1 preintegration transcription using the Rev-dependent Rev-CEM cell reveals a sizable transcribing DNA population comparable with proviral templates. J Virol 2009.

  45. Philippe S, Sarkis C, Barkats M, Mammeri H, Ladroue C, Petit C et al. Lentiviral vectors with a defective integrase allow efficient and sustained transgene expression in vitro and in vivo. Proc Natl Acad Sci USA 2006; 103: 17684–17689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Vargas Jr J, Klotman ME, Cara A . Conditionally replicating lentiviral-hybrid episomal vectors for suicide gene therapy. Antiviral Res 2008; 80: 288–294.

    Article  CAS  PubMed  Google Scholar 

  47. Vargas Jr J, Gusella GL, Najfeld V, Klotman ME, Cara A . Novel integrase-defective lentiviral episomal vectors for gene transfer. Hum Gene Ther 2004; 15: 361–372.

    Article  CAS  PubMed  Google Scholar 

  48. Wu Y, Beddall MH, Marsh JW . Rev-dependent indicator T cell line. Curr HIV Res 2007; 5: 395–403.

    Google Scholar 

  49. Wu Y, Beddall MH, Marsh JW . Rev-dependent lentiviral expression vector. Retrovirology 2007; 4: 12.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Naldini L, Blomer U, Gallay P, Ory D, Mulligan R, Gage FH et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 1996; 272: 263–267.

    Article  CAS  PubMed  Google Scholar 

  51. Fisher KS, Maxwell IH, Murphy JR, Collier J, Glode LM . Construction and expression of plasmids containing mutated diphtheria toxin A-chain-coding sequences. Infect Immun 1991; 59: 3562–3565.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Maxwell F, Maxwell IH, Glode LM . Cloning, sequence determination, and expression in transfected cells of the coding sequence for the tox 176 attenuated diphtheria toxin A chain. Mol Cell Biol 1987; 7: 1576–1579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kohno K, Uchida T . Highly frequent single amino acid substitution in mammalian elongation factor 2 (EF-2) results in expression of resistance to EF-2-ADP-ribosylating toxins. J Biol Chem 1987; 262: 12298–12305.

    CAS  PubMed  Google Scholar 

  54. Gelderblom HC, Vatakis DN, Burke SA, Lawrie SD, Bristol GC, Levy DN . Viral complementation allows HIV-1 replication without integration. Retrovirology 2008.

  55. Perez VL, Rowe T, Justement JS, Butera ST, June CH, Folks TM . An HIV-1-infected T cell clone defective in IL-2 production and Ca2+ mobilization after CD3 stimulation. J Immunol 1991; 147: 3145–3148.

    CAS  PubMed  Google Scholar 

  56. He J, Choe S, Walker R, Di Marzio P, Morgan DO, Landau NR . Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity. J Virol 1995; 69: 6705–6711.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Marsden MD, Zack JA . Eradication of HIV: current challenges and new directions. J Antimicrob Chemother 2009; 63: 7–10.

    Article  CAS  PubMed  Google Scholar 

  58. Chun TW, Davey Jr RT, Engel D, Lane HC, Fauci AS . Re-emergence of HIV after stopping therapy (in process citation). Nature 1999; 401: 874–875.

    Article  CAS  PubMed  Google Scholar 

  59. Gaur M, Leavitt AD . Mutations in the human immunodeficiency virus type 1 integrase D,D(35)E motif do not eliminate provirus formation. J Virol 1998; 72: 4678–4685.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Leavitt AD, Robles G, Alesandro N, Varmus HE . Human immunodeficiency virus type 1 integrase mutants retain in vitro integrase activity yet fail to integrate viral DNA efficiently during infection. J Virol 1996; 70: 721–728.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Aquaro S, Calio R, Balzarini J, Bellocchi MC, Garaci E, Perno CF . Macrophages and HIV infection: therapeutical approaches toward this strategic virus reservoir. Antiviral Res 2002; 55: 209–225.

    Article  CAS  PubMed  Google Scholar 

  62. Stellbrink HJ, Hufert FT, Tenner-Racz K, Lauer J, Schneider C, Albrecht H et al. Kinetics of productive and latent HIV infection in lymphatic tissue and peripheral blood during triple-drug combination therapy with or without additional interleukin-2. Antivir Ther 1998; 3: 209–214.

    CAS  PubMed  Google Scholar 

  63. Chun TW, Engel D, Mizell SB, Hallahan CW, Fischette M, Park S et al. Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy (see comments). Nat Med 1999; 5: 651–655.

    Article  CAS  PubMed  Google Scholar 

  64. Karin M, Lin A . NF-kappaB at the crossroads of life and death. Nat Immunol 2002; 3: 221–227.

    Article  CAS  PubMed  Google Scholar 

  65. Greene C, O’Neill L . Interleukin-1 receptor-associated kinase and TRAF-6 mediate the transcriptional regulation of interleukin-2 by interleukin-1 via NFkappaB but unlike interleukin-1 are unable to stabilise interleukin-2 mRNA. Biochim Biophys Acta 1999; 1451: 109–121.

    Article  CAS  PubMed  Google Scholar 

  66. Matsumura T, Degawa T, Takii T, Hayashi H, Okamoto T, Inoue J et al. TRAF6-NF-kappaB pathway is essential for interleukin-1-induced TLR2 expression and its functional response to TLR2 ligand in murine hepatocytes. Immunology 2003; 109: 127–136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Goor RS, Pappenheimer Jr AM . Studies on the mode of action of diphtheria toxin. 3. Site of toxin action in cell-free extracts. J Exp Med 1967; 126: 899–912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Collier RJ . Effect of diphtheria toxin on protein synthesis: inactivation of one of the transfer factors. J Mol Biol 1967; 25: 83–98.

    Article  CAS  PubMed  Google Scholar 

  69. Collier RJ . Diphtheria toxin: mode of action and structure. Bacteriol Rev 1975; 39: 54–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Collier RJ . Understanding the mode of action of diphtheria toxin: a perspective on progress during the 20th century. Toxicon 2001; 39: 1793–1803.

    Article  CAS  PubMed  Google Scholar 

  71. Potala S, Sahoo SK, Verma RS . Targeted therapy of cancer using diphtheria toxin-derived immunotoxins. Drug Discov Today 2008; 13: 807–815.

    Article  CAS  PubMed  Google Scholar 

  72. Woo JH, Liu YY, Mathias A, Stavrou S, Wang Z, Thompson J et al. Gene optimization is necessary to express a bivalent anti-human anti-T cell immunotoxin in Pichia pastoris. Protein Expr Purif 2002; 25: 270–282.

    Article  CAS  PubMed  Google Scholar 

  73. Foley GE, Lazarus H, Farber S, Uzman BG, Boone BA, McCarthy RE . Continuous culture of human lymphoblasts from peripheral blood of a child with acute leukemia. Cancer 1965; 18: 522–529.

    Article  CAS  PubMed  Google Scholar 

  74. Neville Jr DM, Scharff J, Hu HZ, Rigaut K, Shiloach J, Slingerland W et al. A new reagent for the induction of T-cell depletion, anti-CD3-CRM9. J Immunother Emphasis Tumor Immunol 1996; 19: 85–92.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the George Mason University Student Health Center for blood donations; the NIH AIDS Research & Reference Reagent Program, NIAID, NIH, for reagents; David M Neville for his help on DT-A cloning and discussions; Jeffrey Guo and Wei Ao for technical assistance; and Jennifer Guernsey for editorial assistance. This work was supported by Public Health Service Grant NS051130 (to YW) from NINDS and AI069981, AI081568 (to YW) from NIAID. Yanfang Zheng was supported by the generous donations of the donors and riders of the 2008 NYCDC AIDS ride organized by Marty Rosen and Day2 Inc.

Author information

Author notes

  1. Z Wang, Z Tang and Y Zheng: These authors contributed equally to this work.

Authors and Affiliations

  1. Transplantation Biology Research Center,

    Z Wang

  2. , Massachusetts General Hospital, Harvard Medical School, Harvard University, Boston, MA, USA

    Z Wang

  3. Department of Molecular and Microbiology, George Mason University, Manassas, VA, USA

    Z Tang, Y Zheng, D Yu, M Spear, S R Iyer & Y Wu

  4. College of Life Sciences, Shanxi Agriculture University, Shanxi, People's Republic of China

    Z Tang

  5. Department of Chemistry and Biochemistry, George Mason University, Manassas, VA, USA

    B Bishop

Authors
  1. Z Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Z Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Spear
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S R Iyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B Bishop
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Wu.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on Gene Therapy website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, Z., Tang, Z., Zheng, Y. et al. Development of a nonintegrating Rev-dependent lentiviral vector carrying diphtheria toxin A chain and human TRAF6 to target HIV reservoirs. Gene Ther 17, 1063–1076 (2010). https://doi.org/10.1038/gt.2010.53

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2010.53

Keywords

This article is cited by

Search

Advanced search

Quick links