Primer unblocking and rescue of DNA synthesis by azidothymidine (AZT)-resistant HIV-1 reverse transcriptase: comparison between initiation and elongation of reverse transcription and between (-) and (+) strand DNA synthesis

The Journal of Biological Chemistry
Mickael RigourdR Marquet

Abstract

Azidothymidine (AZT) is a widely used inhibitor of type 1 human immunodeficiency virus reverse transcriptase (RT) that acts as chain terminator. Upon treatment, mutations conferring AZT resistance to RT are gradually selected. It has been shown that resistant RT is able to unblock the AZT-terminated primer by an ATP-dependent mechanism. However, this resistance mechanism has only been demonstrated for DNA-dependent DNA elongation. Here, we compared the AZT resistance of mutant RT during DNA elongation on DNA and RNA templates. We showed that, during DNA elongation, primer unblocking and rescue of DNA synthesis take place with similar rate constants on DNA and RNA templates. However, the fraction of a primer eventually repaired during RNA-dependent DNA synthesis is 2x lower compared with that of DNA-dependent synthesis, leading to reduced resistance. We also compared the initiation of reverse transcription, which uses tRNA(3)(Lys) as a primer and displays characteristic kinetic features, and the subsequent RNA-dependent elongation. Unlike during elongation, resistant RT was unable to unblock the AZT-terminated primer during initiation of (-) DNA strand synthesis. Our results demonstrate that the efficiency of primer unblocking c...Continue Reading

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Citations

Jan 31, 2009·Nature Reviews. Drug Discovery·Jia JiaYu Zong Chen
Apr 1, 2008·Journal of Photochemistry and Photobiology. B, Biology·J F NeaultH A Tajmir-Riahi
Mar 1, 2012·PloS One·Jessica H BrehmUNKNOWN AIDS Clinical Trials Group Study 175 Protocol Team
Jul 7, 2012·Biochimie·Céline DuclouxCatherine Isel
Apr 23, 2013·Current Opinion in Virology·Kalyan Das, Eddy Arnold
Jan 1, 2010·Viruses·Catherine IselRoland Marquet
Dec 21, 2007·Journal of Biomolecular Structure & Dynamics·J F NeaultH A Tajmir-Riahi
Dec 9, 2004·DNA and Cell Biology·Amin Ahmed OuameurHeidar-Ali Tajmir-Riahi
Jan 30, 2021·SAHARA J : Journal of Social Aspects of HIV/AIDS Research Alliance·Argyo DemartotoSiti Zunariyah

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