Combination of peptide protease inhibitor and recombinant interferon-alpha A synergistically inhibited acute and chronic HIV-1 infection in vitro.

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Combination of peptide protease inhibitor and recombinant interferon-alpha A synergistically inhibited acute and chronic HIV-1 infection in vitro.

Abstr Gen Meet Am Soc Microbiol. 1994;94:485 (abstract no. T-15). Unique Identifier : AIDSLINE ASM94/94313093
Pagano PJ; Chong KT; Upjohn Laboratories, Kalamazoo, MI.

Abstract: Effective treatment of human immunodeficiency virus (HIV) infections may require combinations of agents that attack different molecular targets in the viral replicative cycle. We investigated the effect of combining U-75875, a peptide protease inhibitor containing a non-hydrolyzable dihydroxyethylene isostere, with recombinant human interferon-alpha A (alpha IFN). HIV-1 infected cells (H9 cells infected with HIV-1 IIIB; human peripheral blood mononuclear cells infected with a clinical isolate, HIV-1 JRCSF) were cultured in the presence of test compounds and drug effects on HIV-1 p24 antigen level in supernatant were measured by an ELISA assay. Drug interactions were then evaluated by the MacSynergy method of Prichard and Shipman and by the median effect principle using the combination index-isobologram technique of Chou and Talalay. Over a range of drug concentrations (U-75875 at 0.003, 0.01, 0.03, and 0.1 microM and alpha IFN at 3, 10, 30, and 100 IU/ml), U-75875 in combination with alpha IFN synergistically inhibited the replication of HIV-1 by both methods of synergy analysis. No significant cytotoxicity was observed in the MTT assay at the highest concentrations of each agent tested. We conclude that the combination of U-75875 and alpha interferon is synergistic against both acute and chronic HIV-1 replication in vitro.

Keywords: Cell Survival/DRUG EFFECTS Cells, Cultured Dose-Response Relationship, Drug Drug Synergism Human HIV Core Protein p24/ANALYSIS/BIOSYNTHESIS HIV Protease Inhibitors/*TOXICITY HIV-1/*DRUG EFFECTS/PHYSIOLOGY Interferon Alfa, Recombinant/*TOXICITY Monocytes/CYTOLOGY/DRUG EFFECTS Oligopeptides/*TOXICITY Virus Replication/*DRUG EFFECTS ABSTRACT
941030
M94A0861

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