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J. Biol. Chem., Vol. 279, Issue 1, 509-516, January 2, 2004
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Mechanistic Basis for Reduced Viral and Enzymatic Fitness of HIV-1 Reverse Transcriptase Containing Both K65R and M184V Mutations*
From the
Architecture et Fonction des Macromolécules Biologiques, UMR 6098 CNRS et Université Aix-Marseille I et II, ESIL, Campus de Luminy, 13288 Marseille cedex 09, France, ¶Gilead Sciences, Inc., Foster City, California, ||ViroLogic, Inc., S. San Francisco, California, and **Genosciences, Marseille, France
HIV-1 drug resistance mutations are often inversely correlated with viral fitness, which remains poorly described at the molecular level. Some resistance mutations can also suppress resistance caused by other resistance mutations. We report the molecular mechanisms by which a virus resistant to lamivudine with the M184V reverse transcriptase mutation shows increased susceptibility to tenofovir and can suppress the effects of the tenofovir resistance mutation K65R. Additionally, we report how the decreased viral replication capacity of resistant viruses is directly linked to their decreased ability to use natural nucleotide substrates and that combination of the K65R and M184V resistance mutations leads to greater decreases in viral replication capacity. All together, these results define at the molecular level how nucleoside-resistant viruses can be driven to reduced viral fitness.
Received for publication, August 8, 2003 , and in revised form, October 1, 2003.
* This investigation was supported in part by the Agence Nationale de Recherche sur le SIDA (ANRS), and Ensemble Contre le SIDA (ECS). 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 predoctoral fellowship from the Agence Nationale de Recherche sur le SIDA (ANRS).
Supported by a postdoctoral fellowship from Ensemble Contre le SIDA.
To whom correspondence should be addressed. E-mail: bruno{at}afmb.cnrs-mrs.fr.
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