Nuclease-resistant phosphorothioate analogs of certain oligodeoxynucleotides have been tested in vitro as antiviral agents against human immunodeficiency virus (HIV) in human T-cells. Phosphorothioate analogs complementary to HIV sequences, as well as non-complementary analogs including homo-oligomers, exhibited potent antiviral activity. The antiviral activity was related to the base composition of the analogs, and longer phosphorothioates were more effective than shorter ones. A 28- mer phosphorothioate oligodeoxycytidine (S-dC28) at a concentration of 1uM exhibited potent antiviral activity and inhibited de novo viral DNA synthesis as shown by Southern blot analysis. However, S-dC28 failed to inhibit gag expression in chronically infected T-cells assessed by immunofluorescent assay at concentrations up to 25uM. An N3-methylthymidine-containing phosphorothioate analog, which does not hybridize efficiently in vitro to complementary normal DNA, showed no antiviral activity. A 14-mer phosphorothioate oligodeoxycytidine (S-dC14) synergistically enhanced the antiviral activity of 2', 3'- dideoxyadenosine, an anti-HIV nucleoside. Therefore, phosphorothioate analogs of oligodeoxynucleotides could represent a novel class of experimental therapeutic agents against the acquired immunodeficiency syndrome (AIDS) and related diseases. However, their mechanism of action is likely to be complex.
