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.
de Jong
M D
MD
Department of Virology, Academic Medical Centre, University of Amsterdam, The Netherlands. m.Jong@amc.uva.nl
Schuurman
R
R
Lange
J M
JM
Boucher
C A
CA
D003062:Codon; D003545:Cysteine / Q000235:genetics; D004352:Drug Resistance, Microbial; D005500:Follow-Up Studies; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D009154:Mutation; D019829:Nevirapine / Q000494:pharmacology / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D011533:Proviruses / Q000187:drug effects / Q000235:genetics; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D014443:Tyrosine / Q000235:genetics; D019562:Viral Load
D003062:Codon; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D014443:Tyrosine; D019829:Nevirapine; D003545:Cysteine