1. McGill University AIDS Centre, Montreal, Canada
2. Inst. Biochemical Research, Moscow, Russia.

We have studied the anti-HIV effect of a novel 5'-hydrogen phosphonate of AZT, termed Phosphazid, and have shown that the IC50 for this compound in regard to both laboratory and clinical strains of HIV, using both cell lines and primary cultures, is about 10-fold higher than that of AZT (IC50 range 0.01 - 0.1 uM vs. 0.0005 - 0.01). Extensive cross-resistance was noted in regard to these two compounds, both clinical isolates of HIV containing AZT-resistance-conferring mutations in RT at positions 41, 67, 70 and 215, and recombinant viruses containing these same mutations, alone or in combination, displayed similar fold-resistance against both AZT and Phosphazid. In contrast, tissue culture selection experiments, performed with cell lines, revealed that it was more difficult to select for resistance against Phosphazid than against AZT, with maximal levels of resistance to the former compound attained at drug concentrations about 15 times above the IC50. Cloning and sequencing of the RT gene revealed only one mutation site consistently associated with diminished sensitivity to Phosphazid, D67N, also associated with resistance to AZT. Recombinant viruses containing D67N displayed about 10-fold resistance to Phosphazid. These results demonstrate a distinct resistance profile for Phosphazid in contrast to that for AZT, and may be due to the differences in levels of phosphorylation and intracellular accumulation of intermediate products leading to synthesis of active AZT triphosphate.

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