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

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.

• Authors: J Lisziewicz, D Sun, F F Weichold, A R Thierry, P Lusso, J Tang, R C Gallo, S Agrawal
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 91 Issue 17 Pg. 7942-6 (Aug 16 1994) ISSN: 0027-8424 [Print] United States
• PMID: 8058738 (Publication Type: Journal Article)

Chemical References

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

Topics

• 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)