Nucleic Acids Research, Vol 25, Issue 16 3212-3217, Copyright © 1997 by Oxford University Press
BB Oude Essink, NK Back and B Berkhout
Human immunodeficiency virus type 1 (HIV-1) variants with resistance
mutations in the reverse transcriptase (RT) gene appear during drug therapy
with the nucleoside analogue 2',3'-dideoxy-3'-thiacytidine (3TC). These
3TC-resistant RT variants have a single point mutation that changes the
184Met residue into either Val or Ile. Both codon 184 variants are
frequently observed in 3TC-treated patients and can also be selected in
cell culture infections. We demonstrated previously that the 184Ile and
184Val RT enzymes exhibit a processivity defect in in vitro assays, with
184Ile being the least processive enzyme [Met(wt) >Val >Ile]. In this
study, we measured the polymerase fidelity of the wild-type (184Met) and
3TC-resistant RT enzymes (184Ile and 184Val) on DNA and RNA templates. Both
virion- extracted and Escherichia coli - expressed recombinant RT enzymes
were used to measure the nucleotide misinsertion and mispair extension
efficiencies. The 3TC-resistant enzymes were more accurate than the
wild-type RT protein in both type of assays. The order of accuracy observed
for the codon 184 variants [Ile >Val >Met(wt)] may suggest an inverse
correlation between the fidelity and processivity properties of these
enzymes.
ARTICLES
Increased polymerase fidelity of the 3TC-resistant variants of HIV-1 reverse transcriptase
Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands.
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