Nucleic Acids Research, Vol 26, Issue 7 1713-1717, Copyright © 1998 by Oxford University Press
O Avidan and A Hizi
The reverse transcriptase (RT) of human immunodeficiency virus (HIV)
undergoes rapid mutagenesis due to selective pressure by RT inhibitors
which renders the mutated RT variants resistant to these inhibitors.
Resistance to nucleoside analogs during drug therapy results from point
mutations that lead to specific variations in the RT sequences. It was
recently shown that several well-defined drug-resistant variants of HIV- 1
RT (i.e. Leu74Val, Glu89Gly, Tyr183Phe, Met184Lue, Met184Val and Met184Ile)
show enhanced accuracy of DNA synthesis relative to wild- type HIV-1 RT (as
evident from a reduction in the capacity to introduce mispairs and to
elongate them). Since the last two Met184 variants were shown also to
possess decreased processivity of DNA synthesis, it was recently suggested
that there might be an inverse correlation between the apparent in vitro
fidelity and processivity of DNA synthesis in drug-resistant HIV-1 RT
mutants. In the present study we have conducted a comparative analysis of
the processivity of DNA synthesis on both DNA and RNA templates of the
Leu74Val, Glu89Gly, Tyr183Phe and Met184Leu drug-resistant mutants of HIV-1
RT in comparison with wild-type RT. Apart from the Met184 mutant, which
shows reduced relative processivity (similar to the other mutants of
residue 184 already studied), the other three variants have relative
processivity at least as high as that of wild-type RT. This suggests that
the inverse correlation between reduced processivity and increased fidelity
is restricted only to mutants with modifications of Met184. The results
presented may bear on potential mechanistic and structural differences in
the involvement of the various mutated residues studied in processivity,
fidelity and sensitivity to nucleoside analogs.
ARTICLES
The processivity of DNA synthesis exhibited by drug-resistant variants of human immunodeficiency virus type-1 reverse transcriptase
Department of Cell Biology and Histology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
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