Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 May 1;90(9):3860–3864. doi: 10.1073/pnas.90.9.3860

Long-term treatment of human immunodeficiency virus-infected cells with antisense oligonucleotide phosphorothioates.

J Lisziewicz 1, D Sun 1, V Metelev 1, P Zamecnik 1, R C Gallo 1, S Agrawal 1
PMCID: PMC46405  PMID: 8483903

Abstract

The antiviral activity of antisense oligodeoxynucleotide phosphorothioates complementary to the tat gene, the gag mRNA, and the rev mRNA were studied in a long-term infection model. Three antisense oligonucleotides directed to the splice-acceptor site of the tat gene failed to suppress human immunodeficiency virus type 1 replication at 1 microM concentration in long-term culture. In contrast, two oligodeoxynucleotide phosphorothioates (28-mer) complementary to the gag and the rev mRNAs inhibited viral replication for > 80 days, and the antiviral activity was sequence- and length-dependent. In addition, after pretreatment of cells we could reduce the concentration of the antisense oligodeoxynucleotides by > 10-fold and still maintain the inhibition of viral replication. These results suggest that chemotherapy for human immunodeficiency virus type 1 infection with antisense oligodeoxynucleotide phosphorothioates may be achieved by an initial high-dose treatment followed by a lower maintenance dose.

Full text

PDF
3860

Images in this article

3861Fig. 2
on p.3861
3862Fig. 4
on p.3862

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Agrawal S. Antisense oligonucleotides as antiviral agents. Trends Biotechnol. 1992 May;10(5):152–158. doi: 10.1016/0167-7799(92)90203-8. [DOI] [PubMed] [Google Scholar]
  2. Agrawal S., Goodchild J., Civeira M. P., Thornton A. H., Sarin P. S., Zamecnik P. C. Oligodeoxynucleoside phosphoramidates and phosphorothioates as inhibitors of human immunodeficiency virus. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7079–7083. doi: 10.1073/pnas.85.19.7079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Agrawal S., Ikeuchi T., Sun D., Sarin P. S., Konopka A., Maizel J., Zamecnik P. C. Inhibition of human immunodeficiency virus in early infected and chronically infected cells by antisense oligodeoxynucleotides and their phosphorothioate analogues. Proc Natl Acad Sci U S A. 1989 Oct;86(20):7790–7794. doi: 10.1073/pnas.86.20.7790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Agrawal S., Tang J. Y. GEM 91--an antisense oligonucleotide phosphorothioate as a therapeutic agent for AIDS. Antisense Res Dev. 1992 Winter;2(4):261–266. doi: 10.1089/ard.1992.2.261. [DOI] [PubMed] [Google Scholar]
  5. Agrawal S., Tang J. Y., Sun D., Sarin P. S., Zamecnik P. C. Synthesis and anti-HIV activity of oligoribonucleotides and their phosphorothioate analogs. Ann N Y Acad Sci. 1992 Oct 28;660:2–10. doi: 10.1111/j.1749-6632.1992.tb21052.x. [DOI] [PubMed] [Google Scholar]
  6. Agrawal S., Temsamani J., Tang J. Y. Pharmacokinetics, biodistribution, and stability of oligodeoxynucleotide phosphorothioates in mice. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7595–7599. doi: 10.1073/pnas.88.17.7595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Goodchild J., Agrawal S., Civeira M. P., Sarin P. S., Sun D., Zamecnik P. C. Inhibition of human immunodeficiency virus replication by antisense oligodeoxynucleotides. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5507–5511. doi: 10.1073/pnas.85.15.5507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Letsinger R. L., Zhang G. R., Sun D. K., Ikeuchi T., Sarin P. S. Cholesteryl-conjugated oligonucleotides: synthesis, properties, and activity as inhibitors of replication of human immunodeficiency virus in cell culture. Proc Natl Acad Sci U S A. 1989 Sep;86(17):6553–6556. doi: 10.1073/pnas.86.17.6553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Lisziewicz J., Sun D., Klotman M., Agrawal S., Zamecnik P., Gallo R. Specific inhibition of human immunodeficiency virus type 1 replication by antisense oligonucleotides: an in vitro model for treatment. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11209–11213. doi: 10.1073/pnas.89.23.11209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Matsukura M., Zon G., Shinozuka K., Robert-Guroff M., Shimada T., Stein C. A., Mitsuya H., Wong-Staal F., Cohen J. S., Broder S. Regulation of viral expression of human immunodeficiency virus in vitro by an antisense phosphorothioate oligodeoxynucleotide against rev (art/trs) in chronically infected cells. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4244–4248. doi: 10.1073/pnas.86.11.4244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ratner L., Haseltine W., Patarca R., Livak K. J., Starcich B., Josephs S. F., Doran E. R., Rafalski J. A., Whitehorn E. A., Baumeister K. Complete nucleotide sequence of the AIDS virus, HTLV-III. Nature. 1985 Jan 24;313(6000):277–284. doi: 10.1038/313277a0. [DOI] [PubMed] [Google Scholar]
  12. Sarin P. S., Agrawal S., Civeira M. P., Goodchild J., Ikeuchi T., Zamecnik P. C. Inhibition of acquired immunodeficiency syndrome virus by oligodeoxynucleoside methylphosphonates. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7448–7451. doi: 10.1073/pnas.85.20.7448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Shibahara S., Mukai S., Morisawa H., Nakashima H., Kobayashi S., Yamamoto N. Inhibition of human immunodeficiency virus (HIV-1) replication by synthetic oligo-RNA derivatives. Nucleic Acids Res. 1989 Jan 11;17(1):239–252. doi: 10.1093/nar/17.1.239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Stein C. A., Tonkinson J. L., Yakubov L. Phosphorothioate oligodeoxynucleotides--anti-sense inhibitors of gene expression? Pharmacol Ther. 1991 Dec;52(3):365–384. doi: 10.1016/0163-7258(91)90032-h. [DOI] [PubMed] [Google Scholar]
  15. Stevenson M., Iversen P. L. Inhibition of human immunodeficiency virus type 1-mediated cytopathic effects by poly(L-lysine)-conjugated synthetic antisense oligodeoxyribonucleotides. J Gen Virol. 1989 Oct;70(Pt 10):2673–2682. doi: 10.1099/0022-1317-70-10-2673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Temsamani J., Tang J. Y., Agrawal S. Capped oligodeoxynucleotide phosphorothioates. Pharmacokinetics and stability in mice. Ann N Y Acad Sci. 1992 Oct 28;660:318–320. doi: 10.1111/j.1749-6632.1992.tb21099.x. [DOI] [PubMed] [Google Scholar]
  17. Vickers T., Baker B. F., Cook P. D., Zounes M., Buckheit R. W., Jr, Germany J., Ecker D. J. Inhibition of HIV-LTR gene expression by oligonucleotides targeted to the TAR element. Nucleic Acids Res. 1991 Jun 25;19(12):3359–3368. doi: 10.1093/nar/19.12.3359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Zaia J. A., Rossi J. J., Murakawa G. J., Spallone P. A., Stephens D. A., Kaplan B. E., Eritja R., Wallace R. B., Cantin E. M. Inhibition of human immunodeficiency virus by using an oligonucleoside methylphosphonate targeted to the tat-3 gene. J Virol. 1988 Oct;62(10):3914–3917. doi: 10.1128/jvi.62.10.3914-3917.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Zamecnik P. C., Goodchild J., Taguchi Y., Sarin P. S. Inhibition of replication and expression of human T-cell lymphotropic virus type III in cultured cells by exogenous synthetic oligonucleotides complementary to viral RNA. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4143–4146. doi: 10.1073/pnas.83.12.4143. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES