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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 90 ·No. 9 ·1993-05-01 ·Pages 3860-4

Lisziewicz J, Sun D, Metelev V, Zamecnik P, Gallo RC, Agrawal S

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.

Related Genes

gag rev

MeSH Terms

Antiviral Agents/pharmacology Base Sequence Cell Line Dose-Response Relationship, Drug Genes, gag Genes, rev HIV-1/drug effects,genetics,physiology Humans Kinetics Molecular Sequence Data Oligonucleotides, Antisense/pharmacology T-Lymphocytes Thionucleotides/pharmacology Time Factors Virus Replication/drug effects

Chemicals

Antiviral Agents Oligonucleotides, Antisense Thionucleotides

Authors & Affiliations

6 authors, click to expand affiliations / ORCID

Lisziewicz J

Laboratory of Tumor Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20853.

Sun D

Metelev V

Zamecnik P

Gallo R C

Agrawal S

References (19)

19 references, click to expand

Complete nucleotide sequence of the AIDS virus, HTLV-III.
Nature. 1985 Jan 24-30;313(6000):277-84 PMID: 2578615
Capped oligodeoxynucleotide phosphorothioates. Pharmacokinetics and stability in mice.
Ann N Y Acad Sci. 1992 Oct 28;660:318-20 PMID: 1340145
Inhibition of human immunodeficiency virus replication by antisense oligodeoxynucleotides.
Proc Natl Acad Sci U S A. 1988 Aug;85(15):5507-11 PMID: 3041414
Inhibition of human immunodeficiency virus by using an oligonucleoside methylphosphonate targeted to the tat-3 gene.
J Virol. 1988 Oct;62(10):3914-7 PMID: 2458490
Oligodeoxynucleoside phosphoramidates and phosphorothioates as inhibitors of human immunodeficiency virus.
Proc Natl Acad Sci U S A. 1988 Oct;85(19):7079-83 PMID: 3174622
Inhibition of acquired immunodeficiency syndrome virus by oligodeoxynucleoside methylphosphonates.
Proc Natl Acad Sci U S A. 1988 Oct;85(20):7448-51 PMID: 3174646
Inhibition of human immunodeficiency virus (HIV-1) replication by synthetic oligo-RNA derivatives.
Nucleic Acids Res. 1989 Jan 11;17(1):239-52 PMID: 2911465
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):4244-8 PMID: 2471199
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):6553-6 PMID: 2771942
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):2673-82 PMID: 2794975
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):7790-4 PMID: 2682627
Inhibition of HIV-LTR gene expression by oligonucleotides targeted to the TAR element.
Nucleic Acids Res. 1991 Jun 25;19(12):3359-68 PMID: 2062653
Pharmacokinetics, biodistribution, and stability of oligodeoxynucleotide phosphorothioates in mice.
Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7595-9 PMID: 1881900
Phosphorothioate oligodeoxynucleotides--anti-sense inhibitors of gene expression?
Pharmacol Ther. 1991 Dec;52(3):365-84 PMID: 1668180
Antisense oligonucleotides as antiviral agents.
Trends Biotechnol. 1992 May;10(5):152-8 PMID: 1368317
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):11209-13 PMID: 1454800
GEM 91--an antisense oligonucleotide phosphorothioate as a therapeutic agent for AIDS.
Antisense Res Dev. 1992 Winter;2(4):261-6 PMID: 1363378
Synthesis and anti-HIV activity of oligoribonucleotides and their phosphorothioate analogs.
Ann N Y Acad Sci. 1992 Oct 28;660:2-10 PMID: 1340121
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):4143-6 PMID: 3012555

Article Info

Journal

Proceedings of the National Academy of Sciences of the United States of America

Abbr.

Proc Natl Acad Sci U S A

ISSN

0027-8424

DOI

10.1073/pnas.90.9.3860

Published

1993-05-01

Pages

3860-4

Language

English

Region

United States

NLM ID

7505876

PMCID

PMC46405

Subset

External Links

PubMed source DOI: 10.1073/pnas.90.9.3860 PMC Full Text View journal details

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

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