SWITCH TO UNUSUAL AMINO-ACIDS AT CODON-215 OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE-TRANSCRIPTASE GENE IN SEROCONVERTORS INFECTEDWITH ZIDOVUDINE-RESISTANT VARIANTS

Sequences of the human immunodeficiency virus type 1 (HIV-1) reverse t ranscriptase (RT) domain were determined by direct sequencing of HIV-1 RNA in successive plasma samples from eight seroconverting patients i nfected with virus bearing the T215Y/F amino acid substitution associa ted with zidovudine (ZDV) resistance. At baseline, additional mutation s associated with ZDV resistance were detected. Three patients had the M41L amino acid change, which persisted. Two patients had both the D6 7N and the K70R amino acid substitutions; reversion to the wild type w as seen at both positions in one of these patients and at codon 70 in the other one. Reversion to the wild type at codon 215 was observed in only one of eight patients. Unusual amino acids, such as aspartic aci d (D) and cysteine (C), appeared at position 215 in four patients duri ng follow-up. These variants isolated by coculturing were sensitive to ZDV, Overgrowth of these variants suggests that they have better fitn ess than the original T215Y variant. Intraindividual nucleoside substi tutions over time were 10 times more frequent in codons associated wit h ZDV resistance (41, 67, 70, 215, and 219) than in other codons of th e RT domain. The predominance of nonsynonymous substitutions observed over time suggests that most changes reflect adaptation of the RT func tion. The variance in sequence evolution observed among patients, in p articular at codon 215, supports a role for chance in the evolution of the RT domain.