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 comba t HIV-1 infection may offer an alternative to traditional pharmacologi cal therapies, We compared the effects of two 28-mer antisense phospho rothioate oligodeoxynucleotides [PS-oligo(dN)] with non-sequence-speci fic controls on HIV-1 replication in long-term human monocyte/macropha ge and PBMC cultures, The anti-rev PS-oligo(dN) was complementary to t he 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 t o 10.0 mu M for a period of 20 days. Cell survival was 100% at 0.1 mu M, but decreased to 5% at 10.0 mu M in relation to the untreated contr ol cultures, Our data demonstrate that replication of both the T cell tropic and macrophage-tropic HIV-1 strains in primary cells can be inh ibited by PS-oligo(dN) in a sequence-specific and dose-dependent manne r at concentrations achievable in vivo, However, the sequence-dependen t antiviral activity of the utilized PS-oligo(dN) was limited to a win dow of specificity at concentrations between 0.25 and 1.0 mu M.