Antisense phosphorothioate oligodeoxynucleotides alter HIV type 1 replication in cultured human macrophages and peripheral blood mononuclear cells.
The use of antisense oligodeoxynucleotides as antiviral drugs to combat HIV-1 infection may offer an alternative to traditional pharmacological therapies. We compared the effects of two 28-mer antisense phosphorothioate oligodeoxynucleotides [PS-oligo(dN)] with non-sequence-specific controls on HIV-1 replication in long-term human monocyte/macrophage and PBMC cultures. The anti-rev PS-oligo(dN) was complementary to the messenger RNA (mRNA) sequences derived from the overlapping region of the HIV-1 regulatory genes tat and rev, while anti-gag targeted the translational initiation site of the gag mRNA. In vitro cytotoxicity of the PS-oligo(dN) was evaluated at concentrations ranging from 0.1 to 10.0 microM for a period of 20 days. Cell survival was 100% at 0.1 microM, but decreased to 5% at 10.0 microM in relation to the untreated control cultures. Our data demonstrate that replication of both the T cell-tropic and macrophage-tropic HIV-1 strains in primary cells can be inhibited by PS-oligo(dN) in a sequence-specific and dose-dependent manner at concentrations achievable in vivo. However, the sequence-dependent antiviral activity of the utilized PS-oligo(dN) was limited to a window of specificity at concentrations between 0.25 and 1.0 microM.
Weichold
F F
FF
Laboratory of Tumor Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Lisziewicz
J
J
Zeman
R A
RA
Nerurkar
L S
LS
Agrawal
S
S
Reitz
M S
MS
Gallo
R C
RC
D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015757:Genes, rev; D015756:Genes, tat; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008214:Lymphocytes / Q000821:virology*; D008264:Macrophages / Q000821:virology*; D009000:Monocytes / Q000821:virology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000502:physiology; D013873:Thionucleotides; D013997:Time Factors; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides