NATURAL OCCURRENCE OF DRUG-RESISTANCE MUTATIONS IN THE REVERSE-TRANSCRIPTASE OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ISOLATES

Reverse transcriptase-associated amino acid substitutions related to d dC, d4T, and nevirapine resistance have been found in isolates of huma n immunodeficiency virus type 1 (HIV-1) from patients treated with AZT only. Sequence analysis of 23 isolates documented the presence of 4 u nexpected mutations at amino acid residues related to drug resistance. Two isolates contained an aspartic residue in codon 69 associated wit h ddC resistance, and another a change in codon 75 associated with res istance to d4T. The Y-to-C alteration in codon 181 associated with nev irapine resistance was observed in another isolate after serial passag e in cell culture in the absence of drug. Changes in substitution patt erns were also noted after serial passage of four AZT resistant isolat es in cell culture without inhibitors. One of the strains showed chang es in codons 67 and 70 to wild-type residues. Clonal analysis showed t hat this alteration occurred by the selection during cell culture pass age of the wild-type genotype, which was present as a minority subpopu lation in the initially resistant virus stock, rather than to genetic reversion. In summary, we present evidence documenting the presence of mutations associated with drug resistance in the absence of drug trea tment and supporting the role played by genetic variability in the eme rgence of HIV-1 antiviral resistance.