Synergistic inhibition of HIV-1 by an antisense oligonucleotide and nucleoside analog reverse transcriptase inhibitors.
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.
Veal
G J
GJ
Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Agrawal
S
S
Byrn
R A
RA
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
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D015683:Gene Products, gag; D016376:Oligonucleotides, Antisense; D018894:Reverse Transcriptase Inhibitors; D013873:Thionucleotides