PMID: 9557711Apr 29, 1998Paper

Increased misincorporation fidelity observed for nucleoside analog resistance mutations M184V and E89G in human immunodeficiency virus type 1 reverse transcriptase does not correlate with the overall error rate measured in vitro

Journal of Virology
W C Drosopoulos, Vinayaka R Prasad

Abstract

Nucleoside analog-resistant variants of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) that displayed higher in vitro polymerase fidelity were previously identified via nucleotide insertion and mispair extension assays. To evaluate the contribution of increased nucleotide insertion and primer extension fidelities on the overall error rate of HIV-1 RT, we have measured the impact of two such mutations, E89G and M184V, on DNA copying fidelity in an M13 phage-based forward mutation assay. Using this assay, we observed mutation frequencies of 8.60 x 10(-3), 6.26 x 10(-3), 5.53 x 10(-3), and 12.30 x 10(-3) for wild-type, E89G, M184V, and double-mutant E89G/M184V HIV-1 RTs, respectively. Therefore, the overall polymerase fidelities of wild-type, E89G, M184V, and E89G/M184V HIV-1 RTs are similar (less than twofold differences) for DNA-dependent DNA synthesis. Thus, rather large increases in fidelity of deoxynucleoside triphosphate insertion and mispair extension observed previously appear not to influence the overall error rate of these mutants. However, a qualitative analysis of the mutations induced revealed significant differences in the mutational spectra between the wild-type and mutant enzymes.

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Citations

Mar 21, 2000·Medicinal Research Reviews·H JonckheereE De Clercq
Apr 5, 2002·Clinical Microbiology Reviews·Robert W Shafer
Jul 12, 2005·Antiviral Chemistry & Chemotherapy·Prem L SharmaRaymond F Schinazi
May 20, 2003·Proceedings of the National Academy of Sciences of the United States of America·Julie K Pfeiffer, Karla Kirkegaard
Dec 4, 2009·AIDS Research and Human Retroviruses·Raphael W LihanaHiroshi Ichimura
Jul 18, 2002·Proceedings of the National Academy of Sciences of the United States of America·Wen-Hui ZhangVinay K Pathak
Jan 21, 2006·The Journal of Biological Chemistry·Monica E HamburghVinayaka R Prasad
Sep 25, 1999·The Journal of Biological Chemistry·M WisniewskiR A Bambara
Feb 22, 2012·The FEBS Journal·Verónica BarrioluengoLuis Menéndez-Arias
Jun 13, 2012·Microbiology and Molecular Biology Reviews : MMBR·Esteban DomingoCelia Perales
Aug 16, 2001·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Lee T. Bacheler
Jun 25, 2015·Microbiology Spectrum·Stephen H Hughes
Feb 16, 2011·Journal of Molecular Biology·Varuni K Jamburuthugoda, Thomas H Eickbush

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