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Research Article

Modeling HIV-1 Drug Resistance as Episodic Directional Selection

  • Ben Murrell,

    Affiliations: Biomedical Informatics Research Division, eHealth Research and Innovation Platform, Medical Research Council, Tygerberg, South Africa, Computer Science Division, Department of Mathematical Sciences, Stellenbosch University, Stellenbosch, South Africa

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  • Tulio de Oliveira,

    Affiliations: Africa Centre for Health and Population Studies, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa, Research Department of Infection and Population Health, University College London, London, United Kingdom

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  • Chris Seebregts,

    Affiliations: Biomedical Informatics Research Division, eHealth Research and Innovation Platform, Medical Research Council, Tygerberg, South Africa, School of Computer Science, University of KwaZulu-Natal, Durban, South Africa

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  • Sergei L. Kosakovsky Pond,

    Affiliation: Department of Medicine, University of California San Diego, San Diego, California, United States of America

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  • Konrad Scheffler mail,

    kscheffler@ucsd.edu

    Affiliations: Computer Science Division, Department of Mathematical Sciences, Stellenbosch University, Stellenbosch, South Africa, Department of Medicine, University of California San Diego, San Diego, California, United States of America

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  • on behalf of the Southern African Treatment and Resistance Network (SATuRN) Consortium
  • Published: May 10, 2012
  • DOI: 10.1371/journal.pcbi.1002507

Reader Comments (1)

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Concern over HIV drug resistance is overblown.

Posted by drasnick on 10 May 2012 at 23:43 GMT

The concern about anti-HIV drug resistance is overblown. This is especially true for inhibitors of 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.

The general misunderstanding regarding the significance of the inhibitor-resistant mutants can be attributed in large part to the common practice of testing the mutant proteases against a single substrate without taking into consideration the eight sequential cleavages necessary for viable maturation of HIV. It is extremely unlikely that mutations of the enzyme, substantial enough to protect the protease against inhibition, will at the same time leave virtually unimpaired its proteolytic activity towards all eight cleavages (Rasnick 1997). None of the inhibitor-resistant mutant HIV proteases reported so far (even in the absence of inhibitors) has come anywhere near the minimum level of overall catalytic activity necessary for infectious, viable virus. Thus, inhibitor-resistant mutant HIV proteases are very unlikely to contribute to viral viability in vivo.

Therefore, traumatizing patients with the specter of drug-resistant mutants of HIV resulting from a failure to adhere to a Draconian regimen of medication is unjustified. It is important to emphasize that the protease inhibitors are toxic compounds, with a growing list of serious and life-threatening consequences. Finally, the deceptively named “viral-load” test does not measure infectious virus and should not be used to indicate the presence of viable, infectious HIV in patients.


David Rasnick, PhD

Rasnick D (1997) Kinetics analysis of consecutive HIV proteolytic cleavages of the Gag-Pol polyprotein. J Biol Chem 272: 6348-6353.

No competing interests declared.

RE: Concern over HIV drug resistance is overblown.

Mark_rushton replied to drasnick on 11 May 2012 at 12:10 GMT

RE: Concern over HIV drug resistance is overblown.

kscheffler replied to drasnick on 12 May 2012 at 21:15 GMT

The existence of fringe groups denying the benefits of HIV medication, along with the serious harm that has been caused by their attitude, is well known. We find it regrettable that a poster would abuse a scientific forum to raise a dubious point that has no relevance to the substantive (methodological) contribution of our work.

Konrad Scheffler and co-authors

No competing interests declared.