INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ACTIVITY IN-VITRO BY OLIGONUCLEOTIDES COMPOSED ENTIRELY OF GUANOSINE AND THYMIDINE

Oligonucleotide compounds composed of only deoxyguanosine and deoxythy midine were able to significantly inhibit human immunodeficiency virus type-1 (HIV-1)-induced syncytium formation and virus production (as m easured by p24 core antigen expression) in an acute infection assay sy stem. The oligonucleotides did not share any homology with or possess any complementary (antisense) sequence motifs to the HIV-1 genome. The guanosine/ thymidine-containing oligonucleotides (GTOs) that showed t his anti-HIV activity contained natural phosphodiester (PD) linkages ( backbones) between the nucleosides. One of the PD oligonucleotide sequ ence motifs tested was capable of inhibiting HIV-1-induced syncytium f ormation and p24 production with a median effective dose in culture (E D(50)) in the submicromolar range. In addition, oligonucleotides teste d were able to significantly suppress HIV-1 p24 levels greater than or equal to 7 days after removal of the drug from the infected cell cult ure medium. The growth inhibition properties (toxicity) of this genre of oligonucleotides was determined to be well above the ED(50) values yielding high selective indexes. In vitro results showed that GTOs wit h PD backbones were potent competitive inhibitors of HIV-1 reverse tra nscriptase. These same molecules were capable of blocking the interact ion between gp120 and CD4. All measured activities of these molecules were increased by factors of 10-500 when the PD backbone was replaced with a PT backbone in a sequence-dependent manner. The enhanced antivi ral activity displayed by the sulfur group on the oligonucleotide back bone and the lack of any sequence-specific interactions suggest that a percentage of antiviral activity of oligonucleotide-based therapeutic s is due to mechanisms other than those originally postulated for olig onucleotides. The good selective index of GTOs coupled with the prolon ged suppression of HIV-1 in culture after removal of oligonucleotides from the infected cell culture make this a class of compounds that war rant investigation as therapeutic agents to be used against HIV-1.