Replication of a pre-existing resistant HIV-1 subpopulation in vivo after introduction of a strong selective drug pressure

Recent reports indicate a high rate of viral replication during all phases of HIV-1 infection. This rapid turnover presents a continuous drive towards mutations in the HIV-1 genome, which may include those conferring drug resistance. Although the natural occurrence of drug-resistant variants has been reported, the implication on viral kinetics of the subsequent introduction of a selective pressure, in the form of antiviral treatment, remains to be elucidated. We analysed proviral DNA from nine previously untreated participants in a nevirapine study for the presence of the nevirapine resistance-conferring tyrosine to cysteine substitution at codon 181 of HIV-1 reverse transcriptase. In one individual, a minor proviral subpopulation containing this mutation was detected. A rapid selective outgrowth of this minor drug-resistant subpopulation during subsequent treatment with nevirapine was evidenced by a nearly complete replacement of the wild-type HIV-1 RNA population by 181-cysteine variant virus in serum within 1 week, and a reversal of the proportions of tyrosine- and cysteine-encoding proviruses within 2 weeks of treatment, which contrasted with other subjects tested. The rapid emergence of a drug-resistant virus variant clearly resulted in a lack of replication inhibition by nevirapine: whereas other patients demonstrated a median 1.2 log10 decrease in serum HIV-1 RNA load during the first week of treatment, an increase of 0.6 log10 was observed in this patient. The extensive repercussions for subsequent treatment of even a minor subpopulation of naturally occurring drug-resistant variants observed in this study must be considered in future therapeutic strategies