In vitro evaluation of mismatched double-stranded RNA (ampligen) for combination therapy in the treatment of acquired immunodeficiency syndrome.
Multiple drug effect analyses with mismatched double-stranded RNA (mismatched dsRNA or Ampligen) as a core drug were performed to identify other agents and mechanisms through which mismatched dsRNA may potentiate effective therapeutic intervention in human immunodeficiency virus (HIV) infection. Antiviral activities were defined by a microtiter infection assay utilizing MT-2 cells as targets and HTLV-III-B produced in H9 cells as a virus source. The scope of agents tested included rIFN-alpha A, rIFN-beta Ser 17, and rIFN-gamma as cytokines; azidothymidine and phosphonoformate (Foscarnet) as inhibitors of reverse transcription; ribavirin as a putative inhibitor of proper HIV mRNA capping; amphotericin B as a lipophile; and castanospermine as a glycoprotein processing (glucosidase I) inhibitor. Separately, each drug demonstrated dose-dependent anti-HIV activity and, when used in combination with mismatched dsRNA, demonstrated synergism. Although mismatched dsRNA was synergistic with all three IFNs for anti-HIV activity in microtiter infection assays, it did not potentiate the transient inhibition of virus production observed for IFN in cultures of H9/HTLV-III-B cells. The results of these studies suggest that the pleiotropic activities of dsRNAs differ from those of IFN and may provide synergism in combination therapy with a wide range of antiviral drugs for the treatment of the acquired immunodeficiency syndrome (AIDS).
Montefiori
D C
DC
Department of Pathology, Vanderbilt University, School of Medicine, Nashville, TN 37232.
Robinson
W E
WE
Mitchell
W M
WM
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000470:Alkaloids / Q000494:pharmacology; D000666:Amphotericin B / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D017245:Foscarnet; D006678:HIV / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D066298:In Vitro Techniques; D007212:Indolizines; D007370:Interferon Type I / Q000494:pharmacology; D000068556:Interferon beta-1a; D000068576:Interferon beta-1b; D016899:Interferon-beta; D007371:Interferon-gamma / Q000494:pharmacology; D007372:Interferons / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012254:Ribavirin / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology; D054836:Indolizidines
D000470:Alkaloids; D000666:Amphotericin B; D000998:Antiviral Agents; D017245:Foscarnet; D007212:Indolizines; D007370:Interferon Type I; D000068556:Interferon beta-1a; D000068576:Interferon beta-1b; D016899:Interferon-beta; D007371:Interferon-gamma; D007372:Interferons; D010746:Phosphonoacetic Acid; D012330:RNA, Double-Stranded; D011994:Recombinant Proteins; D012254:Ribavirin; D015215:Zidovudine; C037806:castanospermine; D054836:Indolizidines