title: Synergistic inhibition of HIV-1 by an antisense oligonucleotide and nucleoside analog reverse transcriptase inhibitors.
abstract: We have studied the effects of the gag antisense phosphorothioate oligonucleotide GEM 91 and mismatch antisense controls on the antiviral activities of ddC and other nucleoside analogs in HIV-infected MT-4 cells using a cytoprotection based assay. Under standard assay conditions, i.e. simultaneous incubation of drugs, HIV-1 IIIB and MT-4 cells, both GEM 91 and mismatch controls interacted synergistically with ddC resulting in an approximate 40-fold decrease in the IC50 value of ddC; this suggests a potent but sequence non-specific effect of GEM 91. Under post-adsorption assay conditions, i.e. pre-incubation of virus and cells and removal of excess HIV before drug addition, GEM 91 exhibited synergism with ddC, with an approximate 5-fold decrease in ddC IC50 value. This favorable interaction was not seen with any of the mismatch oligonucleotides, suggesting the involvement of a sequence-specific mechanism of action. Similar results were seen with the thymidine analogs AZT and d4T in combination with GEM 91. These data suggest a potential role for GEM 91 and future sequence-specific antisense drugs in combination with nucleoside analogs for the treatment of HIV infection. It is essential that potential interactions between new and existing classes of anti-HIV drugs are studied extensively as antiretroviral drug combinations become increasingly more complex.
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Veal
authors.forename: S
authors.initials: S
authors.lastname: Agrawal
authors.forename: R A
authors.initials: RA
authors.lastname: Byrn
mesh_terms: D000327:Adsorption; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D015224:Dideoxynucleosides / Q000494:pharmacology*; D004357:Drug Synergism; D015683:Gene Products, gag / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000633:toxicity; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013873:Thionucleotides / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D015683:Gene Products, gag; D016376:Oligonucleotides, Antisense; D018894:Reverse Transcriptase Inhibitors; D013873:Thionucleotides