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M110836200v1
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Papers In Press, published online ahead of print March 18, 2002
J. Biol. Chem, 10.1074/jbc.M110836200
Submitted on November 12, 2001
Revised on March 18, 2002
Accepted on March 15, 2002

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

Mickaël Rigourd, Chantal Ehresmann, Michael A. Parniak, Bernard Ehresmann, and Roland Marquet

UPR 9002 du CNRS, IBMC, Strasbourg cedex 67084

Corresponding Author: r.marquet{at}ibmc.u-strasbg.fr

Azidothymidine (AZT) is a widely used inhibitor of HIV-1 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 primer eventually repaired during RNA-dependent DNA synthesis is twice lower as compared to DNA-dependent synthesis, leading to reduced resistance. We also compared the initiation of reverse transcription, which uses tRNA3Lys as 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 conferred by the AZT resistance mutations greatly vary during the different steps of the provirus synthesis. They also suggest that inhibitors specifically targeting the initiation of reverse transcription might reveal advantageous, as compared to elongation inhibitors.


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