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Updated: May 31, 2026
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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Accessory mutations maintain stability in drug-resistant HIV-1 protease
1Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Journal of Molecular Biology
|July 19, 2011
Summary
Drug resistance mutations in human immunodeficiency virus (HIV) protease destabilize the enzyme. Accessory mutations can restore protease stability, aiding HIV adaptation and explaining mutation prevalence in drug resistance evolution.
Area of Science:
- Biochemistry
- Virology
- Evolutionary Biology
Background:
- The evolution of drug resistance in human immunodeficiency virus (HIV) is a complex process.
- Understanding the mechanisms behind HIV-1 protease resistance is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the impact of HIV-1 protease resistance mutations on protein stability.
- To identify mutations that can compensate for the destabilizing effects of resistance mutations.
Main Methods:
- Analysis of clinical HIV isolates.
- Assessment of protein stability and enzyme activity in relation to mutations.
Main Results:
- Accumulation of resistance mutations significantly destabilizes HIV-1 protease.
- Specific accessory mutations were identified that restore or enhance protease stability.
- Resistance mutations reduce protease activity at neutral pH, while stabilizing mutations improve pH tolerance.
Conclusions:
- Protein stability is a critical factor in the evolution of HIV-1 drug resistance.
- Compensatory mutations play a significant role in overcoming the fitness costs associated with resistance.
- Findings explain the distribution of mutations in HIV protease and inform future therapeutic strategies.
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