Antisense oligodeoxynucleotide phosphorothioate complementary to Gag mRNA blocks replication of human immunodeficiency virus type 1 in human peripheral blood cells.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 91 ·No. 17 ·1994-08-16 ·Pages 7942-6

Lisziewicz J, Sun D, Weichold FF, Thierry AR, Lusso P, Tang J, Gallo RC, Agrawal S

Abstract

Gene-expression modulator 91 (GEM91) is a 25-nt antisense oligodeoxynucleotide phosphorothioate complementary to the Gag mRNA of human immunodeficiency virus type 1 (HIV-1). Cellular uptake and intracellular distribution of GEM91 within cells suggest that this oligomer is readily available for antisense activity. GEM91 inhibited HIV-1 replication in a dose-dependent and sequence-specific manner. In a comparative study, 2 microM GEM91 was as effective as 5 microM 3'-azido-3'-deoxythymidine in blocking virus replication during the 28-day treatment of an HIV-1-infected T-cell line. GEM91 also completely inhibited (> 99%) the growth of three different HIV-1 isolates in primary lymphocytes and prevented the cytopathic effect of the virus in primary CD4+ T cells. Similarly, treatment with GEM91 for 3 weeks of HIV-1/BaL-infected primary macrophages blocked virus replication. Based on GEM91 anti-HIV-activity, safety, and pharmacokinetic profile in animals, a clinical trial was started using this compound as an antisense oligonucleotide drug for the treatment of the acquired immunodeficiency syndrome.

MeSH Terms

Antigens, CD/biosynthesis Antiviral Agents/toxicity Base Sequence Biological Transport CD4 Antigens/biosynthesis CD8 Antigens/biosynthesis Cell Line Cells, Cultured Flow Cytometry Gene Products, gag/biosynthesis Genes, gag HIV-1/drug effects,physiology Humans Kinetics Lymphocytes/cytology,drug effects,microbiology Macrophages/cytology,microbiology Molecular Sequence Data Oligodeoxyribonucleotides, Antisense Oligonucleotides, Antisense/pharmacokinetics,toxicity RNA, Messenger/drug effects Thionucleotides/pharmacokinetics,toxicity Virus Replication/drug effects

Chemicals

Antigens, CD Antiviral Agents CD4 Antigens CD8 Antigens Gene Products, gag Oligodeoxyribonucleotides, Antisense Oligonucleotides, Antisense RNA, Messenger Thionucleotides GEM91

Authors & Affiliations

8 authors, click to expand affiliations / ORCID

Lisziewicz J

Laboratory of Tumor Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

Sun D

Weichold F F

Thierry A R

Lusso P

Tang J

Gallo R C

Agrawal S

References (26)

26 references, click to expand

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
Intracellular availability of unmodified, phosphorothioated and liposomally encapsulated oligodeoxynucleotides for antisense activity.
Nucleic Acids Res. 1992 Nov 11;20(21):5691-8 PMID: 1454532
Cellular uptake and subcellular distribution of phosphorothioate oligonucleotides into cultured cells.
Antisense Res Dev. 1992 Fall;2(3):211-22 PMID: 1490072
Functional sites in the 5' region of human immunodeficiency virus type 1 RNA form defined structural domains.
J Mol Biol. 1993 Jan 20;229(2):382-97 PMID: 8429553
GEM 91--an antisense oligonucleotide phosphorothioate as a therapeutic agent for AIDS.
Antisense Res Dev. 1992 Winter;2(4):261-6 PMID: 1363378
Long-term treatment of human immunodeficiency virus-infected cells with antisense oligonucleotide phosphorothioates.
Proc Natl Acad Sci U S A. 1993 May 1;90(9):3860-4 PMID: 8483903
Antisense oligonucleotides as therapeutic agents--is the bullet really magical?
Science. 1993 Aug 20;261(5124):1004-12 PMID: 8351515
Phylogenetic analysis of gag genes from 70 international HIV-1 isolates provides evidence for multiple genotypes.
AIDS. 1993 Jun;7(6):769-80 PMID: 8363755
Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide.
Proc Natl Acad Sci U S A. 1978 Jan;75(1):280-4 PMID: 75545
Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS.
Science. 1984 May 4;224(4648):497-500 PMID: 6200935
Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS.
Science. 1984 May 4;224(4648):500-3 PMID: 6200936
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
The role of mononuclear phagocytes in HTLV-III/LAV infection.
Science. 1986 Jul 11;233(4760):215-9 PMID: 3014648
Envelope sequences of two new United States HIV-1 isolates.
Virology. 1988 Jun;164(2):531-6 PMID: 3369091
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
Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds.
J Virol Methods. 1988 Aug;20(4):309-21 PMID: 2460479
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 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
Stimulatory effect of counterflow centrifugal elutriation in large-scale separation of peripheral blood monocytes can be reversed by storing the cells at 37 degrees C.
J Clin Apher. 1991;6(1):48-53 PMID: 1646202
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
Fifth mutation in human immunodeficiency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine.
Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1934-8 PMID: 1371886
The human immunodeficiency virus type 1 packaging signal and major splice donor region have a conserved stable secondary structure.
J Virol. 1992 Jul;66(7):4144-53 PMID: 1602537
Phosphorothioate oligodeoxynucleotides--anti-sense inhibitors of gene expression?
Pharmacol Ther. 1991 Dec;52(3):365-84 PMID: 1668180
On the historical origins of HIV-1 (MN) and (RF).
AIDS Res Hum Retroviruses. 1992 Sep;8(9):1539-41 PMID: 1457197

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.91.17.7942

Published

1994-08-16

Pages

7942-6

Language

English

Region

United States

NLM ID

7505876

PMCID

PMC44520

Subset

External Links

PubMed source DOI: 10.1073/pnas.91.17.7942 PMC Full Text View journal details

Analysis Services

Antisense oligodeoxynucleotide phosphorothioate complementary to Gag mRNA blocks replication of human immunodeficiency virus type 1 in human peripheral blood cells.

Contact

WeChat Official Account