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Research Article

A Novel Substrate-Based HIV-1 Protease Inhibitor Drug Resistance Mechanism

  • Monique Nijhuis,

    Affiliation: Eijkman Winkler Center, Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands

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  • Noortje M van Maarseveen,

    Affiliation: Eijkman Winkler Center, Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands

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  • Stephane Lastere,

    Affiliation: APHP-Hopital Bichat, Laboratoire Virologie, Paris, France

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  • Pauline Schipper,

    Affiliation: Eijkman Winkler Center, Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands

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  • Eoin Coakley,

    Affiliation: Monogram Biosciences, San Francisco, California, United States of America

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  • Bärbel Glass,

    Affiliation: Department of Virology, University of Heidelberg, Heidelberg, Germany

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  • Mirka Rovenska,

    Affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Science of the Czech Republic, Prague, Czech Republic

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  • Dorien de Jong,

    Affiliation: Eijkman Winkler Center, Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands

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  • Colombe Chappey,

    Affiliation: Monogram Biosciences, San Francisco, California, United States of America

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  • Irma W Goedegebuure,

    Affiliation: Eijkman Winkler Center, Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands

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  • Gabrielle Heilek-Snyder,

    Affiliation: Roche Bioscience, Palo Alto, California, United States of America

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  • Dominic Dulude,

    Affiliation: Department of Biochemistry, Université de Montreal, Montreal, Canada

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  • Nick Cammack,

    Affiliation: Roche Bioscience, Palo Alto, California, United States of America

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  • Lea Brakier-Gingras,

    Affiliation: Department of Biochemistry, Université de Montreal, Montreal, Canada

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  • Jan Konvalinka,

    Affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Science of the Czech Republic, Prague, Czech Republic

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  • Neil Parkin,

    Affiliation: Monogram Biosciences, San Francisco, California, United States of America

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  • Hans-Georg Kräusslich,

    Affiliation: Department of Virology, University of Heidelberg, Heidelberg, Germany

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  • Francoise Brun-Vezinet,

    Affiliation: APHP-Hopital Bichat, Laboratoire Virologie, Paris, France

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  • Charles A. B Boucher mail

    To whom correspondence should be addressed. E-mail: c.boucher@umcutrecht.nl

    Affiliation: Eijkman Winkler Center, Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands

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  • Published: January 16, 2007
  • DOI: 10.1371/journal.pmed.0040036

About the Authors

Monique Nijhuis, Noortje M van Maarseveen, Pauline Schipper, Dorien de Jong, Irma W Goedegebuure, Charles A. B Boucher
Eijkman Winkler Center, Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands
Stephane Lastere, Francoise Brun-Vezinet
APHP-Hopital Bichat, Laboratoire Virologie, Paris, France
Eoin Coakley, Colombe Chappey, Neil Parkin
Monogram Biosciences, San Francisco, California, United States of America
Bärbel Glass, Hans-Georg Kräusslich
Department of Virology, University of Heidelberg, Heidelberg, Germany
Mirka Rovenska, Jan Konvalinka
Institute of Organic Chemistry and Biochemistry, Academy of Science of the Czech Republic, Prague, Czech Republic
Gabrielle Heilek-Snyder, Nick Cammack
Roche Bioscience, Palo Alto, California, United States of America
Dominic Dulude, Lea Brakier-Gingras
Department of Biochemistry, Université de Montreal, Montreal, Canada

Corresponding Author

Email: c.boucher@umcutrecht.nl

Competing Interests

EC is an employee of Monogram Biosciences.

Author Contributions

MN, SL, BG, IWG, and CABB designed the study. MN, SL, PS, EC, MR, DdJ, CC, IWG, DD, JK, NP, HGK, and FBV analyzed the data. MN, NMvM, SL, EC, BG, CC, GHS, DD, NC, LBG, NP, HGK, FBV, and CBB contributed to writing the paper. MN, NMvM, PS, DdJ, IWG, and FBV collected data or did experiments for the study. SL designed and analyzed the clinical part of the study (i.e., impact of Gag cleavage site mutations on the virological response to highly active antiretroviral therapy). This was investigated for the NARVAL (ANRS 088) trial. FBV was the study leader. BG tested the wild-type and mutant virus in an infectious context, with or without inhibitor, and did the Western blot analysis. MR performed the kinetic analyses of peptide cleavage by HIV protease. GHS provided compound for and helpful discussions about this study. DD designed and did the experiments for measuring the frameshift efficiency of viral variants of this study along with LBG. NP performed analysis of genotypic and phenotypic data relating to gag mutations in clinical samples. HGK performed quantitative immunoblot experiments shown in the paper together with his technician.