A fossil record of zidovudine resistance in transmitted isolates of HIV-1

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Abstract
The introduction of zidovudine (3′-azido-3′-deoxythymidine; AZT; Scheme S1) into clinical practice in 1987 ushered in the therapeutic era of the AIDS epidemic. Not long thereafter, isolation of an AZT-resistant variant of HIV type 1 (HIV-1) was reported (1). Work by several groups demonstrated the association between emergence of AZT resistance and disease progression in patients receiving antiretroviral therapy (2–4). High-level AZT resistance requires mutations at reverse transcriptase (RT) codons 41, 67, 70, 210, 215, and 219, which emerge in an ordered fashion (5, 6). The K70R mutation usually is the first to emerge. Although this mutation produces only a modest decrease in drug susceptibility, K70R mutants are selected rapidly after initiation of AZT (7). Subsequently, variants with mutations at codon 215 emerge and replace the K70R mutants. A likely explanation for the slower emergence of mutants carrying T215Y or F substitutions is the requirement for a double-nucleotide mutation at this codon [215T(ACC) to 215Y(TAC) or 215F(TTC), respectively]. Transmission of an AZT-resistant isolate of HIV-1 was first reported in 1992 (8). Recent studies show a prevalence of AZT resistance mutations in viral sequences from newly infected individuals of 5–10% (9, 10), documenting a dramatic increase in the transmission of AZT-resistant HIV-1 over the past decade. In the absence of continued selective pressure from AZT-containing therapy, resistant variants eventually are replaced by AZT-susceptible revertants. Such revertants frequently involve the substitution at codon 215 of unusual amino acids such as aspartate, asparagine, cysteine, or serine in place of the mutant and wild-type residues more commonly encountered at this position. The 215D(GAC), 215N(AAC), 215C(TGC), and 215S(TCC) variants can each arise as a result of single nucleotide changes from 215Y or -F and appear to be more common than wild-type …

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