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Nucleic Acids Research 2006 34(1):42-52; doi:10.1093/nar/gkj411
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Published online 3 January 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

Mg2+ dependency of HIV-1 reverse transcription, inhibition by nucleoside analogues and resistance

Valérie Goldschmidt, Joël Didierjean, Bernard Ehresmann, Chantal Ehresmann, Catherine Isel and Roland Marquet*

Unité Propre de Recherche 9002 du CNRS conventionnée à l'Université Louis Pasteur, IBMC 15 rue René Descartes, 67084 Strasbourg cedex, France

*To whom correspondence should be addressed. Tel: +33 3 88 41 70 54; Fax: +33 3 88 60 22 18; Email: r.marquet{at}ibmc.u-strasbg.fr

Received August 26, 2005. Revised December 7, 2005. Accepted December 7, 2005.

Metal ions are essential for DNA polymerase and RNase H activities of HIV-1 reverse transcriptase (RT). RT studies are routinely performed at 6–8 mM Mg2+, despite the fact that the in vivo concentration might be as low as 0.2 mM. We studied the influence of MgCl2 and ATP, which likely binds a significant fraction of the magnesium pool in vivo, on the DNA polymerase and RNase H activities of HIV-1 RT, its inhibition by nucleoside RT inhibitors (NRTIs) and primer unblocking by AZT-resistant RT. At low Mg2+ concentration, reverse transcription of a natural template strongly increased despite a dramatically reduced intrinsic polymerase activity under such conditions. Low Mg2+ concentrations affected the RNA stability and indirectly decreased its degradation by the RNase H activity. The reduced RNA degradation prevented premature dissociation of the template and primer strands that otherwise generated dead-end DNA products. In addition, low Mg2+ dramatically decreased the incorporation of NRTIs into DNA and increased nucleotide excision by AZT-resistant RT. The latter effect is also most likely owing to the diminished cleavage of the RNA template. Thus, differences in the free Mg2+ concentration between different cell types or during the cell cycle might strongly affect HIV-1 replication and its inhibition.


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