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J. Biol. Chem., Vol. 278, Issue 42, 40464-40472, October 17, 2003

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The Y181C Substitution in 3'-Azido-3'-deoxythymidine-resistant Human Immunodeficiency Virus, Type 1, Reverse Transcriptase Suppresses the ATP-mediated Repair of the 3'-Azido-3'-deoxythymidine 5'-Monophosphate-terminated Primer^*

Boulbaba Selmi  , Jérôme Deval  ¶, Karine Alvarez , Joëlle Boretto , Simon Sarfati ||, Catherine Guerreiro || and Bruno Canard  **

From the CNRS and Universités d'Aix-Marseille I and II, UMR 6098, Architecture et Fonction des Macromolécules Biologiques, ESIL-Case 925, 163 Avenue de Luminy, 13288 Marseille Cedex 09 and the ^||Institut Pasteur, 28 Rue du Docteur Roux, 75724 Paris Cedex 15, France

Resistance to zidovudine (3'-azido-3'-deoxythymidine, AZT) by the human immunodeficiency virus, type 1, requires multiple amino acid substitutions such as D67N/K70R/T215F/K219Q in the viral reverse transcriptase (RT). In this background of AZT resistance, additional "suppressive" substitutions such as Y181C restore sensitivity to AZT. In order to characterize the mechanism of this AZT resistance suppression, the Y181C substitution was introduced into both wild-type and AZT-resistant reverse transcriptase. The introduction of the Y181C substitution suppresses the increased repair (or unblocking) of the AZTMP-terminated primer provided by the AZT resistance substitutions in RT using either DNA or RNA templates, independently from the RT RNase H activity. Contrary to wild-type RT, the low level of unblocking activity is not due to inhibition by the next correct nucleotide binding to the RT/AZTMP-terminated primer complex. When Y181C is added to the AZT resistance substitutions, ATP binds with less affinity to the AZTMP-terminated primer-RT binary complex. These results provide an insight into one possible molecular mechanism of re-sensitization of AZT-resistant viruses by suppressive substitutions.

Received for publication, March 21, 2003 , and in revised form, July 28, 2003.

^* This work was supported in part by the Agence Nationale de Recherche sur le SIDA and Ensemble Contre le SIDA. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a postdoctoral fellowship from the Ensemble Contre le SIDA.

^¶ Supported by a doctoral fellowship from the Agence Nationale de Recherche sur le SIDA.

^** To whom correspondence should be addressed. Tel.: 33-491-82-86-44; Fax: 33-491-82-86-46; E-mail: bruno{at}afmb.cnrs-mrs.fr.

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