Long-term treatment of human immunodeficiency virus-infected cells with antisense oligonucleotide phosphorothioates.
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.
Lisziewicz
J
J
Laboratory of Tumor Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20853.
Sun
D
D
Metelev
V
V
Zamecnik
P
P
Gallo
R C
RC
Agrawal
S
S
D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015750:Genes, gag; D015757:Genes, rev; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D013601:T-Lymphocytes; D013873:Thionucleotides / Q000494:pharmacology*; D013997:Time Factors; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides