SUSCEPTIBILITIES OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ENZYME AND VIRAL VARIANTS EXPRESSING MULTIPLE RESISTANCE-ENGENDERING AMINO-ACID SUBSTITUTIONS TO REVERSE-TRANSCRIPTASE INHIBITORS

To evaluate the potential that multiply resistant human immunodeficien cy virus type 1 variants may arise during combination nucleoside and n onnucleoside reverse transcriptase inhibitor therapy, we constructed a series of mutant reverse transcriptase enzymes and viruses that coexp ressed various combinations of resistance-associated amino acid substi tutions. Substitutions at residues 100 (Leu-->Ile) and 181 (Tyr-->Cys) , which mediate resistance to the nonnucleosides, suppressed resistanc e to 3'-azido-3'-deoxythymidine (AZT) when coexpressed with AZT-specif ic substitutions. However, a number of viral variants that exhibited s ignificantly reduced susceptibilities to both classes of inhibitors we re constructed.