A mechanism of AZT resistance: An increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase

Peter R. Meyer, Suzanne E. Matsuura, A. Mohsin Mian, Antero G. So, Walter A. Scott

Research output: Contribution to journalArticle

306 Scopus citations

Abstract

Mutations in HIV-1 reverse transcriptase (RT) give rise to 3'-azido-3'- deoxythymidine (AZT) resistance by a mechanism that has not been previously reproduced in vitro. We show that mutant RT has increased ability to remove AZTMP from blocked primers through a nucleotide-dependent reaction, producing dinucleoside polyphosphate and extendible primer. In the presence of physiological concentrations of ATP, mutant RT extended 12% to 15% of primers past multiple AZTMP termination sites versus less than 0.5% for wild type. Although mutant RT also unblocked ddAMP-terminated primers more efficiently than wild-type RT, the removal of ddAMP was effectively inhibited by the next complementary dNTP (IC50 ≃ 12 μM). In contrast, the removal of AZTMP was not inhibited by dNTPs except at nonphysiological concentrations (IC50 > 200 μM).

Original languageEnglish (US)
Pages (from-to)35-43
Number of pages9
JournalMolecular Cell
Volume4
Issue number1
DOIs
StatePublished - Jul 1999

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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