Skip to main content

Advertisement

Springer Nature Link
Log in

Anti-HIV ribozymes

  • Review
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

Abstract

HIV is an RNA virus that replicates intracellularly through various RNA intermediates. Several of these can be targeted by ribozymes (catalytic RNA molecules), and a number of investigators, including this group, have demonstrated the ability of ribozymes to suppress HIV replication in this way. It is argued that this gene therapy approach may be viewed as an adjunct to chemotherapeutic drugs, which may allow not just viral suppression, but also immune restoration. This can only finally be tested in clinical trials, and several are planned. The basic ribozyme unit, the potential of which was described less than 10 years ago, is about to be tested in an amenable disease state.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Baltimore, D. (1995) The enigma of HIV infection.Cell 82, 175,176.

    Article  PubMed  CAS  Google Scholar 

  2. Barré-Sinoussi, F. (1996) HIV as the cause of AIDS.The Lancet 348, 31–35.

    Article  Google Scholar 

  3. McCune, J. M. (1995) Viral latency in HIV disease.Cell 82, 183–188.

    Article  PubMed  CAS  Google Scholar 

  4. Weiss, R. A. (1993) How does HIV cause AIDS?Science 260, 1273–1279.

    Article  PubMed  CAS  Google Scholar 

  5. Johnston, M. I. and Holt, D. F. (1993) Present status and prospects for HIV therapies.Science 260, 1286–1293.

    Article  PubMed  CAS  Google Scholar 

  6. Fauci, A. S. (1993) Multifactorial nature of HIV disease: implications for therapy.Science 262, 1011–1018.

    Article  PubMed  CAS  Google Scholar 

  7. Pantaleo, G., Graziosi, C., Butini, L., Pizzo, P. A., Schnittman, S. M., Kolter, D. P., and Fauci, A. S. (1989) Lymphoid organs function as major reservoirs for human immunodeficiency virus.Proc. Natl. Acad. Sci. USA 88, 9838–9842.

    Article  Google Scholar 

  8. Ho, D. D., Moudgil, T., and Alam, M. (1989) Quantitation of human immunodeficiency virus type 1 in the blood of infected persons.N. Engl. J. Med. 321, 1621–1625.

    Article  PubMed  CAS  Google Scholar 

  9. Saag, M. S., Crain, M. J., Decker, W. D., Campbell-Hill, S., Robinson, S., Brown, W. E., Leuther, M., Whiteley, R. J., Hahn, B. H., and Shaw, G. M. (1991) High-level viremia in adult and children infected with human immunodeficiency virus: relation to disease stage and CD4+ lymphocyte levels.J. Infect. Dis. 164, 72–80.

    PubMed  CAS  Google Scholar 

  10. Clark, S. J., Saag, M. S., Decker, W. D., Campbell-Hill, S., Roberson, J. L., Veldkamp, P. J., Kappes, J. C., Hahn, B. H., and Shaw, G. M. (1991) High titiers of cytopathic virus in plasma of patients with symptomatic primary HIV-1 infection.N. Engl. J. Med. 324, 954–960.

    Article  PubMed  CAS  Google Scholar 

  11. Daar, E. S., Moudgil, T., Meyer, R. D., and Ho, D. D. (1991) Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection.N. Engl. J. Med. 324, 961–964.

    Article  PubMed  CAS  Google Scholar 

  12. Ho, D. D., Neumann, A. U., Perelson, A. S., Chen, W., Leonard, J. M., and Markowitz, M. (1995) Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.Nature (Lond.) 373, 123–126.

    Article  CAS  Google Scholar 

  13. Wei, X., Ghosh, S. K., Taylor, M. E., Johnson V. A., Emini, E. A., Deutsch, P., Lifson, J. D., Bonhoeffer, S., Nowak, M. A., Hahn, B. H., Saag, M. S., and Shaw, G. M. (1995) Viral dynamics in human immunodeficiency virus type 1 infection.Nature (Lond.) 373, 117–122.

    Article  CAS  Google Scholar 

  14. Varmus, H. (1988) Regulation of HIV and HTLV gene expression.Genes & Dev. 2, 1055–1062.

    Article  CAS  Google Scholar 

  15. Trono, D. (1995) HIV accessory proteins: leading roles for the supporting cast.Cell 82, 189–192.

    Article  PubMed  CAS  Google Scholar 

  16. Dimitrov, D. S. (1996) Fusin—a place for HIV-1 and T4 cells to meet.Nature Med. 2, 640,641.

    Article  PubMed  CAS  Google Scholar 

  17. Feng, Y., Broder, C. C., Kennedy, P. E., and Berger, E. A. (1996) HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein coupled receptor.Science 272, 872–876.

    Article  PubMed  CAS  Google Scholar 

  18. Cooper, D. A. and Merigan, T. C. (1996) Clinical treatment.AIDS 10 Supp. A., S133, S134.

    Article  Google Scholar 

  19. Coreh, L. and Holmes, K. K. (1996) Therapy for human immunodeficiency virus infection—what have we learned?N. Engl. J. Med. 335, 1142, 1143.

    Article  Google Scholar 

  20. Bridges, S. H. and Sarver, N. (1995) Gene therapy and immune restoration for HIV disease.The Lancet 345, 427–432.

    Article  CAS  Google Scholar 

  21. Maciejewski, J. P., Weichold, F. F., Young, N. S., Cara, A., Zella, D., Retiz, M. S., Jr, and Gallo, R. C. (1995) Intracellular expression of antibody fragments directed against HIV reverse transcriptase prevents HIV infectionin vitro.Nature Med. 1, 667–673.

    Article  PubMed  CAS  Google Scholar 

  22. Shaheen, F., Duan, L., Zhu, M., Bagasra, O., and Pomerantz, R. J. (1996) Targeting human immuno-deficiency virus type 1 reverse transcriptase by intracellular expression of single-chain variable fragments to inhibit early stages of the viral life cycle.J. Virol. 70, 3392–3400.

    PubMed  CAS  Google Scholar 

  23. Cohen, J. S. (ed.) (1989)Oligodeoxynucleotides: Antisense Inhibitors of Gene Expression. CRC, Boca Raton, FL.

    Google Scholar 

  24. Smythe, J. A. and Symonds, G. (1995) Gene therapeutic agents: the use of ribozymes, antisense and RNA decoys for HIV-1 infection.Inflamm. Res. 44, 11–15.

    Article  PubMed  CAS  Google Scholar 

  25. Escaich, S., Kalfoglou, C., Plavec, I., Kaushal, S., Mosca, J. D., and Böhnlein, E. (1995) RevM10-mediated inhibition of HIV-1 replication in chronically infected T cells.Hum. Gene Ther. 6, 625–634.

    PubMed  CAS  Google Scholar 

  26. Woffendin, C., Yang, Z.-Y., Udaykumar, R., Xu, L., Yang, N.-S., Sheehy, M. J., and Nabel, G. J. (1994) Nonviral and viral delivery of a human immunodeficiency virus protective gene into primary human T cells.Proc. Natl. Acad. Sci. USA 91, 11,581–11,585.

    Article  CAS  Google Scholar 

  27. Caputo, A., Grossi M. P., Bozzini, R., Rossi, C., Betti, M., Marconi, P. C., Barbanti-Brodano, G., and Balboni, P. G. (1996) Inhibition of HIV-1 replication and reactivation from latency by tat transdominant negative mutants in the cysteine rich region.Gene Ther. 3, 235–245.

    PubMed  CAS  Google Scholar 

  28. Lisziewicz, J., Sun, D., Lisziewicz, A., and Gallo, R. C. (1995) Antitat gene therapy: a candidate for latestage AIDS patients.Gene Ther. 2, 218–222.

    PubMed  CAS  Google Scholar 

  29. Aguilar-Cordova, E., Chinen, J., Donehower, L. A., Harper, J. W., Rice, A. P., Butel, J. S., and Belmont, J. W. (1995) Inhibition of HIV-1 by a double transdominant fusion gene.Gene Ther. 2, 181–186.

    PubMed  CAS  Google Scholar 

  30. Lee, S. W., Gallardo, H. F., Gilboa, E., and Smith, C. (1994) 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.J. Virol. 68, 8254–8264.

    PubMed  CAS  Google Scholar 

  31. Lisziewicz, J., Sun, D., Smythe, J., Lusso, P., Lori, F., Louie, A., Markham, P., Rossi, J., Reitz, M., and Gallo, R. C. (1993) 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 for AIDS,Proc. Natl. Acad. Sci. USA 90, 8000–8004.

    Article  PubMed  CAS  Google Scholar 

  32. Kuwabara, T., Amontov, S. V., Warashina, M., Ohkawa, J., and Taira, K. (1996) Characterization of several kinds of dimer minizyme: simultaneous cleavage at two sites in HIV-1 tat mRNA by dimer minizymes.Nucleic Acids Res. 24, 2302–2310.

    Article  PubMed  CAS  Google Scholar 

  33. Rossi, J. J., Elkins, D., Zaia, J. A., and Sullivan, S. (1992) Ribozymes as anti-HIV-1 therapeutic agents: principles, applications, and problems,AIDS Res. Hum. Retroviruses 8, 183–189.

    Article  PubMed  CAS  Google Scholar 

  34. Sun, L.-Q., Warrilow, D., Wang, L., Witherington, C., Macpherson, J., and Symonds, G. (1994) Ribozyme-mediated suppression of Moloney murine leukemia virus and human immunodeficiency virus type 1 replication in permissive cell lines.Proc. Natl. Acad. Sci. USA 91, 9715–9719.

    Article  PubMed  CAS  Google Scholar 

  35. Sioud, M. and Drlica, K. (1991) Prevention of human immunodeficiency virus type 1 integrase expression inEscherichia coli by a ribozyme.Proc. Natl. Acad. Sci. USA 88, 7303–7307.

    Article  PubMed  CAS  Google Scholar 

  36. Heidenreich, O. and Eckstein, F. (1992) Hammerhead ribozyme-mediated cleavage of the long terminal repeat RNA of human immunodeficiency virus type 1.J. Biol. Chem. 267, 1904–1909.

    PubMed  CAS  Google Scholar 

  37. Crisell, P., Thompson, S., and James, W. (1993) Inhibition of HIV-1 replication by ribozymes that show poor activity in vitro.Nucleic Acids Res. 21, 5251–5255.

    Article  PubMed  CAS  Google Scholar 

  38. Rossi, J. J., Cantin, E. M., Sarver, N., and Chang, P. F. (1991) The potential use of catalytic RNAs in therapy of HIV infection and other diseases.Pharmacol. Ther. 50, 245–254.

    Article  PubMed  CAS  Google Scholar 

  39. Homann, M., Tzortzakaki, S., Rittner, K., Sczakiel, G., and Tabler, M. (1993) Incorporation of the catalytic domain of a hammerhead ribozyme into antisense RNA enhances its inhibitory effect on the replication of human immunodeficiency virus type 1.Nucleic Acids Res. 21, 2809–2814.

    Article  PubMed  CAS  Google Scholar 

  40. Sun, L.-Q., Pyati, J., Smythe, J., Wang, L., Macpherson, J., Gerlach, W., and Symonds, G. (1995) Resistance to human immunodeficiency virus type 1 infection conferred by transduction of human peripheral blood lymphocytes with ribozyme, antisense or polymeric transactivation response element constructs.Proc. Natl. Acad. Sci. USA 92, 7272–7276.

    Article  PubMed  CAS  Google Scholar 

  41. Cech, T. (1987) The chemistry of self-splicing RNA and RNA enzymes.Science 236, 1532–1539.

    Article  PubMed  CAS  Google Scholar 

  42. Uhlenbeck, O. C. (1987) A small catalytic oligoribonucleotide.Nature (Lond.) 328, 596–600.

    Article  CAS  Google Scholar 

  43. Forster, A. and Symons, R. (1987) Self-cleavage of plus and minus RNAs of a virusoid and a structural model for the active sites.Cell 49, 211–220.

    Article  PubMed  CAS  Google Scholar 

  44. Hampel, A., Nesbitt, S., Tritz, R., and Altschuler, M. (1993) The hairpin ribozyme.Methods Enzymol. 5, 37–42.

    Article  CAS  Google Scholar 

  45. Haseloff, J. and Gerlach, W. L. (1988) Simple enzymes with new and highly specific endoribonuclease activity.Nature (Lond.) 334, 585–591.

    Article  CAS  Google Scholar 

  46. Hertel, K. J., Herschlag, D., and Uhlenbeck, O. C. (1996) Specificity of hammerhead ribozyme cleavage.EMBO J. 14, 3751–3757.

    Google Scholar 

  47. Rossi, J. J. (1992) Ribozymes.Curr. Opinion Biotechnol. 3, 3–7.

    Article  CAS  Google Scholar 

  48. James, W. and Al-Shamkhani, A. (1995) RNA enzymes as tools for gene ablation.Curr. Opinion Biotechnol. 6, 44–49.

    Article  CAS  Google Scholar 

  49. Usman, N. and Stinchcomb, D. T. (1996) Design, synthesis, and function of therapeutic hammerhead ribozymes, inCatalytic RNA (Eckstein, F. and Lilley, D. M. J., eds.), Springer, Berlin, pp. 243–264.

    Google Scholar 

  50. Cohen, M. (1990) The in vivo application of ribozymes.TIBTECH,8, 174–179.

    Google Scholar 

  51. Lowenstein, P. and Symonds, G. (1997) Inhibition of Moloney murine leukemia virus by a retroviral vector carrying a ribozyme targeted to the packaging site.J. Gen. Virol., in press.

  52. Sun, L.-Q., Wang, L., Gerlach, W. L., and Symonds, G. (1995) Target sequence-specific inhibition of HIV-1 replication by ribozymes directed to tat RNA.Nucleic Acids Res. 23, 2909–2913.

    Article  PubMed  CAS  Google Scholar 

  53. Koizumi, M., Ozawa, Y., Yagi, R., Nishigaki, T., Kaneko, M., Oka, S-i., Kimura, S., Iwamoto, A., Komatsu, Y., and Ohtsuka, E. (1995) Design and anti-HIV-1 activity of ribozymes that cleave HIV-1 LTR.Nucleic Acids Symp. Ser. 34, 125, 126.

    PubMed  CAS  Google Scholar 

  54. Goodchild, J. and Kohli, V. (1991) Ribozymes that cleave an RNA sequence from human immunodeficiency virus: the effect of flanking sequence on rate.Arch. Biochem. Biophys. 284, 386–391.

    Article  PubMed  CAS  Google Scholar 

  55. Dropulic, B. and Jeang, K.-T. (1994) Intracellular susceptibility to ribozymes in a tethered substrateribozyme provirus model is not predicted by secondary structures of human immunodeficiency virus type 1 RNAsin vitro.Antisense Res. Dev. 4, 217–221.

    PubMed  CAS  Google Scholar 

  56. Tabler, M., Homann, M., Tzortzakaki, S., and Sczakiel, G. (1994) A three-nucleotide helix I is sufficient for full activity of a hammerhead ribozyme: advantages of an asymmetric design.Nucleic Acids Res. 22, 3958–3965.

    Article  PubMed  CAS  Google Scholar 

  57. Homann, M., Tabler, M., Tzortzakaki, S., and Sczakiel, G. (1994) Extension of Helix II of an HIV-1-directed hammerhead ribozyme with long antisense flanks does not alter kinetic parametersin vitro but causes loss of the inhibitory potential in living cells.Nucleic Acids Res. 22, 3951–3957.

    Article  PubMed  CAS  Google Scholar 

  58. Leavitt, M. C., Yu, M., Yamada, O., Kraus, G., Looney, D., Poeschla, E., and Wong-Staal, F. (1994) Transfer of an anti-HIV-1 ribozyme gene into primary human lymphocytes.Hum. Gene Ther. 5, 1115–1120.

    Article  PubMed  CAS  Google Scholar 

  59. Yu, M., Ojwang, J., Yamada, O., Hampel, A., Rapapport, J., Looney, D., and Wong-Staal, F. (1993) A hairpin ribozyme inhibits expression of diverse strains of human immunodeficiency virus type 1.Proc. Natl. Acad. Sci. USA 90, 6340–6344.

    Article  PubMed  CAS  Google Scholar 

  60. Ojwang, J. O., Hampel, A., Looney, D. J., Wong-Staal, F., and Rappaport, J. (1992) Inhibition of human immunodeficiency virus type 1 expression by a hairpin ribozyme.Proc. Natl. Acad. Sci. USA 89, 10,802–10,806.

    Article  CAS  Google Scholar 

  61. Yu, M., Leavitt, M. C., Maruyama, M., Yamada, O., Young, D., Ho, A. D., and Wong-Staal, F. (1995) Intracellular immunization of human fetal cord blood stem/progenitor cells with a ribozyme against human immunodeficiency virus type 1.Proc. Natl. Acad. Sci. USA 92, 699–703.

    Article  PubMed  CAS  Google Scholar 

  62. Yu, M. Poeschla, E., Yamada, O., Degrandis, P., Leavitt, M. C., Heusch, M., Yees, J.-K., Wong-Staal, F., and Hampel, A. (1995) In vitro and in vivo characterization of a second functional hairpin ribozyme against HIV-1.virology 206, 381–386.

    Article  PubMed  CAS  Google Scholar 

  63. Yamada, O., Kraus, G., Leavitt, M. C., Yu, M., and Wong-Staal, F. (1994) Activity and cleavage site specificity of an anti-HIV-1 hairpin ribozyme in human T cells.Virology 205, 121–126.

    Article  PubMed  CAS  Google Scholar 

  64. Chen, C.-J., Banerjea, A. C., Harmison, G. G., Haglund, K., and Schubert, M. (1992) Multitargetribozyme directed to cleave at up to nine highly conserved HIV-1 env RNA regions inhibits HIV-1 replication-potential effectiveness against most presently sequenced HIV-1 isolates.Nucleic Acids Res. 20, 4581–4589.

    Article  PubMed  CAS  Google Scholar 

  65. Sarver, N., Cantin, E. M., Chang, P. S., Zaia, J. A., Ladne, P. A., Stephens, D. A., and Rossi, J. J. (1990) Ribozymes as potential anti-HIV-1 therapeutic agents.Science 247, 1222–1225.

    Article  PubMed  CAS  Google Scholar 

  66. Dropulic, B., Lin, N. H., Martin, M. A., and Jeang, K.-T. (1992) Functional characterization of a U5 ribozyme: intracellular suppression of human immunodeficiency virus type 1 expression.J. Virol. 66, 1432–1441.

    PubMed  CAS  Google Scholar 

  67. Lo, K. M. S., Biasolo, M. A., Dehni, G., Palú, G., and Haseltine, W. A. (1992) Inhibition of replication of HIV-1 by retroviral vectors expressing tat-antisense and anti-tat ribozyme RNA.Virology 190, 176–183.

    Article  PubMed  CAS  Google Scholar 

  68. Weerasinghe, M., Liem, S. E., Asad, S., Read, S. E., and Joshi, S. (1991) Resistance to human immunodeficiency virus type 1 (HIV-1) infection in human CD4+ lymphocyte-derived cell lines conferred by using retroviral vectors expressing an HIV-1 RNA-specific ribozyme.J. Virol. 65, 5531–5534.

    PubMed  CAS  Google Scholar 

  69. Miller, A. D. and Rosman, G. J. (1989) Improved vecors for gene transfer and expression.BioTechniques 7, 980–986.

    PubMed  CAS  Google Scholar 

  70. Jolly, D. (1994) Viral vector systems for gene therapy.Cancer Gene Ther. 1, 51–64.

    PubMed  CAS  Google Scholar 

  71. Kavanaugh, M. P., Miller, D. G., Zhang, W., Law, W., Kozak, S. L., Kabat, D., and Miller, A. D. (1994) Cell-surface receptors for gibbon ape leukemia virus and amphotropic retrovirus are inducible sodium-dependent phosphate symporters.Proc. Natl. Acad. Sci. USA 91, 7071–7075.

    Article  PubMed  CAS  Google Scholar 

  72. Bums, J. C., Friedmann, T., Driever, W., Burrascano, M., and Yee, J. K. (1993) Vesicular stomatititis virus G glycoprotein pseudotyped retroviral vectors: concentration to very high titer and efficient gene transfer into nonmammalian cells.Proc. Natl. Acad. Sci. USA 90, 8033–8037.

    Article  Google Scholar 

  73. Von kalle, C., Kiem, H. P., Goehle, So, Darovsky, B., Heimfeld, S., Torokstorb, B., Storb, R., and Schuening, F. G. (1994) Increased gene transfer into human haematopoietic progenitor cells by extended in vitro exposure to pseudotyped retroviral vector.Blood 84, 2890–2897.

    Google Scholar 

  74. Kuzcyzka, N. (1992) Use of adeno-associated virus as a general transduction vector in mammalian cells.Curr. Top. Microbiol. Immunol. 158, 97–129.

    Google Scholar 

  75. Chatterjee, S., Johnson, P. R., and Wong, K. K., Jr. (1992) Dual-target inhibition of HIV-1in vitro by means of an adeno-associated virus antisense vector.Science 258, 1485–1488.

    Article  PubMed  CAS  Google Scholar 

  76. Carter, D. J. (1992) Adeno-associated virus vectors.Curr. Opinion Biotechnol. 3, 533–539.

    Article  CAS  Google Scholar 

  77. Lever, A. M. L. (1996) HIV and other lentivirus-based vectors.Gene Ther. 3, 470,471.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Johnson & Johnson Research Laboratories, Rushcutter’s Bay, GPO Box 3331, 2001, Sydney, NSW, Australia

    Lun-Quan Sun, Julie A. Ely, Wayne Gerlach & Geoff Symonds

Authors
  1. Lun-Quan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julie A. Ely
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wayne Gerlach
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Geoff Symonds
    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

Sun, LQ., Ely, J.A., Gerlach, W. et al. Anti-HIV ribozymes. Mol Biotechnol 7, 241–251 (1997). https://doi.org/10.1007/BF02740815

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02740815

Index Entries

Search

Navigation