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Research Article

Prediction of Mutational Tolerance in HIV-1 Protease and Reverse Transcriptase Using Flexible Backbone Protein Design

  • Elisabeth Humphris-Narayanan equal contributor,

    equal contributor Contributed equally to this work with: Elisabeth Humphris-Narayanan, Eyal Akiva

    Affiliation: Graduate Group in Biophysics, University of California, San Francisco, San Francisco, California, United States of America

    Current address: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, United States of America

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  • Eyal Akiva equal contributor,

    equal contributor Contributed equally to this work with: Elisabeth Humphris-Narayanan, Eyal Akiva

    Affiliations: California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, California, United States of America, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States of America

    X
  • Rocco Varela,

    Affiliation: Graduate Program in Bioinformatics, University of California, San Francisco, San Francisco, California, United States of America

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  • Shane Ó Conchúir,

    Affiliations: California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, California, United States of America, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States of America

    X
  • Tanja Kortemme mail

    kortemme@cgl.ucsf.edu

    Affiliations: Graduate Group in Biophysics, University of California, San Francisco, San Francisco, California, United States of America, California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, California, United States of America, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States of America, Graduate Program in Bioinformatics, University of California, San Francisco, San Francisco, California, United States of America

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  • Published: August 23, 2012
  • DOI: 10.1371/journal.pcbi.1002639

Reader Comments (1)

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Have computed mutational tolerances been tested for viable, infectious virus?

Posted by drasnick on 24 Aug 2012 at 20:10 GMT

The impressive piece of work leaves me with one important question. Have the mutational tolerances discovered for inhibitor-resistant HIV-1 protease been tested to see if they lead to viable, infectious virus in the absence of inhibitor?

I ask this because to the best of my knowledge, none of the inhibitor-resistant mutants of HIV protease result in viable, infectious virus. The explanation for this phenomenon was provided in: Rasnick D (1997) Kinetics analysis of consecutive HIV proteolytic cleavages of the Gag-Pol polyprotein. J Biol Chem 272: 6348-6353.

The ordered, sequential cleavages of the Gag-Pol polyprotein by HIV protease present the virus with severe limitations on viable mutations of the enzyme. The overall catalytic efficiency of a mutant HIV protease relative to the wild type enzyme is given by the product of the ratios of their respective efficiencies for the 8 obligatory cleavages.

Under no conditions is HIV viable when the geometric mean efficiency of a mutant HIV protease is less than 61% of the wild type activity for each cleavage. The lower catalytic efficiencies of the mutant enzymes coupled with the inverse eighth power dependence on 1/(1 + [I]/Ki) more than offset the inhibitor resistance acquired by HIV protease.

The degree to which the mutant proteases are resistant to inhibitors is meaningful only in the context where the viability and infectivity of the mutant viruses are also quantitated. As the data continue to accumulate, it seems increasingly unlikely that mutations of the HIV protease, substantial enough to protect the enzyme against inhibition, will at the same time leave virtually unimpaired its ordered, sequential processing of all eight cleavage sites of the Gag-Pol polyprotein.

Thus, the inhibitor-resistant mutant HIV proteases are very unlikely to contribute to viral viability in vivo.

Dave Rasnick

No competing interests declared.