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.

  • Acquired Diseases
  • Published:

Inhibition of HIV-1 replication in chronically infected cell lines and peripheral blood mononuclear cells by retrovirus-mediated antitat gene transfer

Gene Therapy volume 7, pages 321–328 (2000)Cite this article

Abstract

Among potential genetic targets for intervention in the HIV-1 life cycle, the tat gene product is a key target. We investigated the ability of an antitat gene to inhibit HIV-1 activation and replication in chronically infected promonocyte (U1) and T cell (ACH-2) lines in vitro. U1 and ACH-2 cells were transduced with an antitat gene expressing RNA with dual (polymeric Tat activation response element and antisense-tat) function that interferes with HIV-1 replication. Tumor necrosis factor-alpha (TNF-α) plus phorbol 12- myristate 13-acetate (PMA)-induced HIV-1 expression, as determined by reverse transcribed PCR and reverse transcriptase (RT) assays, was significantly inhibited in U1 and ACH-2 cells transduced with the antitat gene, compared with the cells transduced with control vector and untransduced cells. This resistance to TNF-α plus PMA-induced HIV-1 expression was demonstrated in antitat gene-transduced U1 and ACH-2 cells maintained in G418-free media for 5 months, suggesting that functional antitat gene may persist for many months in transduced cells and their progeny. Most importantly, we demonstrate that the antitat gene, when introduced into peripheral blood mononuclear cells (PBMC) isolated from patients with HIV-1 infection, inhibited TNF-α plus PMA-induced viral replication as determined by RT-PCR and RT activity. In addition, the antitat gene enhanced the survival of CD4+ T lymphocytes from such patients. These data suggest the feasibility of utilizing antitat gene therapy to block activation and replication of HIV-1 in latently infected monocytes and T- lymphocytes in vivo.

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
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  1. Hammer SM et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team New Engl J Med 1997 337: 725–733

    Article  CAS  Google Scholar 

  2. Gulick RM et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy New Engl J Med 1997 337: 734–739

    Article  CAS  Google Scholar 

  3. Ho D . HIV-1 survives drug onslaught by hiding out T cells Science 1997 278: 122–123

    Google Scholar 

  4. Wong JK et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia Science 1997 278: 1291–1295

    Article  CAS  Google Scholar 

  5. Finzi D et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy Science 1997 278: 1295–1300

    Article  CAS  Google Scholar 

  6. Finzi D et al. 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 

  7. Chun TW et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection Nature 1997 387: 183–188

    Article  CAS  Google Scholar 

  8. Chun TW et al. In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency Nature Med 1995 1: 1284–1290

    Article  CAS  Google Scholar 

  9. Gilboa E, Smith C . Gene therapy for infectious diseases: the AIDS model Trends Genet 1994 10: 139–144

    Article  CAS  Google Scholar 

  10. Yu M, Poeschla E, Wong-Staal F . Progress towards gene therapy for HIV infection Gene Therapy 1994 1: 13–26

    CAS  Google Scholar 

  11. Morgan RA . Gene therapy for HIV infection Clin Exp Immunol 1997 107: 41–44

    Article  CAS  Google Scholar 

  12. Bridges SH, Sarver N . Gene therapy and immune restoration for HIV disease Lancet 1995 345: 427–432

    Article  CAS  Google Scholar 

  13. Lisziewicz J et al. Inhibition of human immunodeficiency virus type 1 replication by regulated expression of a polymeric Tat activation response RNA decoy as a strategy for gene therapy in AIDS Proc Natl Acad Sci USA 1993 90: 8000–8004

    Article  CAS  Google Scholar 

  14. Lisziewicz J, Sun D, Lisziewicz A, Gallo RC . Antitat gene therapy: a candidate for late-stage AIDS patients Gene Therapy 1995 2: 218–222

    CAS  PubMed  Google Scholar 

  15. Lisziewicz J et al. An autoregulated dual-function antitat gene for human immunodeficiency virus type 1 gene therapy J Virol 1995 69: 206–212

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Buonaguro L et al. Effects of the human immunodeficiency virus type 1 Tat protein on the expression of inflammatory cytokines J Virol 1992 66: 7159–7167

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Lafrenie RM et al. Activation of monocytes by HIV-Tat treatment is mediated by cytokine expression J Immunol 1997 159: 4077–4083

    CAS  PubMed  Google Scholar 

  18. Rosenzweig M et al. Transduction of CD34+ hematopoietic progenitor cells with an antitat gene protects T cell and macrophage progeny from AIDS virus infection J Virol 1997 71: 2740–2746

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Levy JA . Pathogenesis of human immunodeficiency virus infection Microbiol Rev 1993 57: 183–289

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Folks TM et al. Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line Science 1987 238: 800–802

    Article  CAS  Google Scholar 

  21. Folks TM et al. Characterization of a promonocyte clone chronically infected with HIV and inducible by 13-phorbol-12-myristate acetate J Immunol 1988 140: 1117–1122

    CAS  PubMed  Google Scholar 

  22. Folks TM et al. Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T cell clone Proc Natl Acad Sci USA 1989 86: 2365–2368

    Article  CAS  Google Scholar 

  23. Chen BK, Saksela K, Andino R, Baltimore D . Distinct modes of human immunodeficiency virus type 1 proviral latency revealed by superinfection of nonproductively infected cell lines with recombinant luciferase-encoding viruses J Virol 1994 68: 654–660

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Poli G, Fauci AS . The effect of cytokines and pharmacologic agents on chronic HIV infection AIDS Res Hum Retrovir 1992 8: 191–197

    Article  CAS  Google Scholar 

  25. Rosenberg ZF, Fauci AS . Immunopathogenesis of HIV infection FASEB J 1991 5: 2382–2390

    Article  CAS  Google Scholar 

  26. Ho WZ et al. Inhibition of HIV type 1 replication in chronically infected monocytes and lymphocytes by retrovirus-mediated gene transfer of anti-Rev single-chain variable fragments AIDS Res Hum Retrovir 1998 14: 1573–1580

    Article  CAS  Google Scholar 

  27. Saksela K et al. High viral load in lymph nodes and latent human immunodeficiency virus (HIV) in peripheral blood cells of HIV-1-infected chimpanzees J Virol 1993 67: 7423–7427

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Chun TW et al. Induction of HIV-1 replication in latently infected CD4+ T cells using a combination of cytokines (published erratum appears in J Exp Med 1998; 188: following 614) J Exp Med 1998 188: 83–91

    Article  CAS  Google Scholar 

  29. Willey RL et al. In vitro mutagenesis identifies a region within the envelope gene of the human immunodeficiency virus that is critical for infectivity J Virol 1988 62: 139–147

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was supported by a W-W Smith grant to W-ZH, and the Frank R Wallace Endowed Chair of The Children's Hospital of Philadelphia (SES) and a Biomed 2 grant (Contract No. BMH4-CT97-2503) to JR.

Author information

Authors and Affiliations

  1. Division of Immunologic and Infectious Diseases, Department of Pediatrics, Joseph Stokes Jr Research Institute of The Children's Hospital of Philadelphia, University of Pennsylvania Medical School, Philadelphia, PA, USA

    Y Li, S E Starr & W-Z Ho

  2. Research Institute for Genetic and Human Therapy (RIGHT), Washington, DC, USA

    J Lisziewicz

  3. Pavia, Italy

    J Lisziewicz

Authors
  1. Y Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S E Starr
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Lisziewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W-Z Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, Y., Starr, S., Lisziewicz, J. et al. Inhibition of HIV-1 replication in chronically infected cell lines and peripheral blood mononuclear cells by retrovirus-mediated antitat gene transfer. Gene Ther 7, 321–328 (2000). https://doi.org/10.1038/sj.gt.3301088

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301088

Keywords

Search

Advanced search

Quick links