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Nucleic Acids Research, Vol 25, Issue 22 4532-4536, Copyright © 1997 by Oxford University Press

ARTICLES

Higher fidelity of RNA-dependent DNA mispair extension by M184V drug- resistant than wild-type reverse transcriptase of human immunodeficiency virus type 1

M Hsu, P Inouye, L Rezende, N Richard, Z Li, VR Prasad and MA Wainberg
Department of Microbiology and Immunology, McGill University, Montreal, Canada.

Reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV- 1) has low fidelity compared with RTs of other retroviruses and cellular DNA polymerases. We and others have previously found that the fidelity of DNA-dependent DNA polymerization (DDDP) of M184V-mutated HIV-1 RT is significantly higher than that of wild-type RT. Viruses containing the M184V substitution are highly resistant to (-)-2'- dideoxy-3'-thiacytidine (3TC) in vitro and in patients treated with 3TC monotherapy. It was of interest to determine the fidelity of RNA- dependent DNA polymerization (RDDP) of M184V RT compared with wild-type because this step occurs first in reverse transcription; errors made during this step may be copied in subsequent polymerization steps. Using an in vitro mispaired primer extension assay, M184V-mutated RT exhibited 3-49-fold decreased frequency of mispair extension compared with wild-type RT. Fidelity differences between M184V and wild-type RT were most marked in extension of A:G (49-fold) and A:C (16-fold) mispairs, with only a marginal (3-fold) decrease in the extension of A:A mispairs. RT containing a methionine to isoleucine (M184I) mutation showed only slight increases in RDDP fidelity compared with wild-type, ranging from 1.5- to 6-fold increases. Of the three RTs tested, wild- type RT was the most error-prone, with mispair extension frequencies ranging from 6.674 x 10(-1) to 7.454 x10(-2).
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