Differential Alteration of the Anti-HIV-1 Effect of Phosphorothioate Oligonucleotide S-dC28 by AZT,Interferon-Alpha,and Dextran Sulfate

Abstract

The combination of S-dC28 (a phosphorothioate oligodeoxcytidine 28 mer) with AZT, recombinant interferon α-A (IFN-αA) or dextran sulfate (DS) against replication of human immunodeficiency virus type 1 (HIV-1) were studied in MT4 cells, using both p24 core antigen and reverse transcriptase (RT) assays. Under the standardized conditions, the anti-HIV-1 dose-effect relationships of all test drugs showed sigmoidal curves with the following EC₅₀ values: for the p24 core antigen assay, S-dC28, 0.03 μM; AZT, 0.004 μM; IFN-αA, 9.2 U/ml; DS, 0.26 μg/ml; for the RT assay, S-dC28, 0.04 μM; AZT, 0.01 μM; IFN-αA, 11.6 U/ml; and DS, 0.31 μg/ml. A computer software based on the median-effect principle and isobologram techniques were used to quantitatively analyze drug interactions by calculating the combination index (CI) where CI < 1, = 1, and > 1 indicates synergism, additive effect and antagonism, respectively. For p24-ELISA, the interaction of S-dC28 and AZT in combination produced a slight antagonism on HIV-1 replicative inhibition with CI values of 1.29-1.10; for RT assays, at EC₅₀-EC₉₅ levels, the CI values are 1.96-1.11. For p24 core antigen assay, the combination of S-dC28 with IFN-αA exhibited a dose-dependent anti-HIV synergism with CI values of 1.15-0.87 at EC₇₅-EC₉₅ levels. The RT assays for the same combination showed a broad synergistic effect with CI values of 0.62-0.60, at EC₅₀-EC₉₅ levels. S-dC28 plus DS showed a nearly additive effect based on both assay methods. The present studies document the lack of synergistic interaction in vitro between S-dC28 and AZT, or S-dC28 and DS. However, S-dC28 and IFN-αA yielded a synergistic effect in which the dose-reduction indices indicate that lower doses of each drug can be used in combination to achieve increased efficacy without detectable cytotoxicity.