Antisense oligodeoxynucleotide phosphorothioate complementary to Gag mRNA blocks replication of human immunodeficiency virus type 1 in human peripheral blood cells.
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.
Lisziewicz
J
J
Laboratory of Tumor Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Sun
D
D
Weichold
F F
FF
Thierry
A R
AR
Lusso
P
P
Tang
J
J
Gallo
R C
RC
Agrawal
S
S
D015703:Antigens, CD / Q000096:biosynthesis; D000998:Antiviral Agents / Q000633:toxicity*; D001483:Base Sequence; D001692:Biological Transport; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D002460:Cell Line; D002478:Cells, Cultured; D005434:Flow Cytometry; D015683:Gene Products, gag / Q000096:biosynthesis*; D015750:Genes, gag; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000382:microbiology*; D008264:Macrophages / Q000166:cytology / Q000382:microbiology*; D008969:Molecular Sequence Data; D020319:Oligodeoxyribonucleotides, Antisense; D016376:Oligonucleotides, Antisense / Q000493:pharmacokinetics / Q000633:toxicity*; D012333:RNA, Messenger / Q000187:drug effects*; D013873:Thionucleotides / Q000493:pharmacokinetics / Q000633:toxicity*; D014779:Virus Replication / Q000187:drug effects*
D015703:Antigens, CD; D000998:Antiviral Agents; D015704:CD4 Antigens; D016827:CD8 Antigens; D015683:Gene Products, gag; D020319:Oligodeoxyribonucleotides, Antisense; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D013873:Thionucleotides; C079996:GEM91