MULTIPLE-DRUG-RESISTANT MUTANTS OF FELINE IMMUNODEFICIENCY VIRUS SELECTED WITH 2',3'-DIDEOXYINOSINE ALONE AND IN COMBINATION WITH 3'-AZIDO-3'-DEOXYTHYMIDINE

Mutants of feline immunodeficiency virus (FIV) were selected in cell c ulture in the continuous presence of 10 muM (each) 3'-azido-3'-deoxyth ymidine (AZT) and 2',3'-dideoxyinosine (ddI). These mutants (AIR-1 and AIR-3) displayed a 13-fold resistance to AZT but had less than a 2-fo ld decrease in susceptibility to ddI. Interestingly, the AIR mutants w ere cross-resistant to phosphonoformate (PFA) and were hypersensitive to 2',3'-dideoxycytidine (ddC). Mutants of FIV were also selected in t he presence of 10 muM ddI alone (DIS-1, DIS-2c), and these displayed a two- to fourfold decrease in susceptibility to ddI. Like the mutants selected with the combination of AZT plus ddI, DIS-1 and DIS-2c were c ross-resistant to PFA and were hypersensitive to ddC. However, they re mained as susceptible as wild-type FIV to AZT. Thus, the mutants selec ted with the combination of AZT plus ddI have phenotypes which reflect those obtained by selection with these drugs individually.