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Assessment of Immunologically Relevant Dynamic Tertiary Structural Features of the HIV-1 V3 Loop Crown R2 Sequence by ab initio Folding
Published on: September 15, 2010
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The evolution of the HIV-1 protease folding stability
David Ferreiro1,2, Ruqaiya Khalil1,2, María J Gallego1,2
1CINBIO, Universidade de Vigo, Vigo 36310, Spain.
Virus Evolution
|January 5, 2023
Summary
Human immunodeficiency virus (HIV-1) protease stability fluctuates within a wide range, accommodating mutations without significantly impacting overall protein evolution or clinical markers. Resistance mutations often maintain stability, aiding viral adaptation.
Area of Science:
- Virology
- Structural Biology
- Evolutionary Biology
Background:
- Protein folding stability typically constrains structural protein evolution.
- The capacity of viral proteins to tolerate mutations affecting stability is poorly understood.
- Human immunodeficiency virus (HIV-1) protease (PR) is a key drug target with an incompletely understood evolutionary stability.
Purpose of the Study:
- To investigate the evolutionary stability of HIV-1 protease under various scenarios.
- To assess the impact of resistance mutations on HIV-1 protease stability.
- To correlate HIV-1 protease stability changes with clinical parameters.
Main Methods:
- Analysis of intra-host and inter-host HIV-1 protease evolution across diverse patient cohorts and subtypes.
- Reconstruction of ancestral HIV-1 protease sequences.
- Evaluation of known HIV-1 protease resistance mutations' effect on folding stability.
Main Results:
- HIV-1 protease stability showed consistent fluctuation within a wide range across all evolutionary scenarios.
- Multiple mutations affecting stability were accommodated while maintaining protease activity.
- No significant correlation was found between HIV-1 protease stability changes and clinical parameters (viral load, CD4+ T-cell counts).
- Approximately half of studied resistance mutations did not significantly decrease stability, facilitating adaptation via compensatory mutations.
Conclusions:
- HIV-1 protease exhibits significant structural plasticity, allowing adaptation without compromising overall stability.
- Viral adaptation can occur without substantial changes in protein folding stability.
- Resistance mutations can be acquired without a major stability penalty, contributing to viral evolution.
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