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Adaptive HIV-1 evolutionary trajectories are constrained by protein stability.
Abayomi S Olabode1, Shaun M Kandathil1,2, Simon C Lovell1
1Evolution & Genomic Sciences, School of Biological Sciences, University of Manchester, Oxford Road, Manchester, UK.
Virus Evolution
|August 31, 2017
Summary
Drug resistance in HIV-1 is a challenge, often involving multiple mutations. Protein structure stability constrains HIV-1 evolution, impacting both resistant and non-resistant mutations.
Area of Science:
- Molecular Biology
- Virology
- Evolutionary Biology
Background:
- HIV-1 drug resistance is a significant clinical challenge, driven by accumulating mutations.
- Epistatic interactions between mutations are crucial for understanding resistance evolution.
- HIV-1's Pol protein is a key target for antiretroviral therapies.
Purpose of the Study:
- To investigate the evolutionary pathways of HIV-1 drug resistance mutations.
- To understand the role of protein structure and stability in HIV-1 evolution.
- To analyze epistatic interactions in the context of HIV-1 drug resistance.
Main Methods:
- Reconstruction of ancestral HIV-1 Pol protein sequences.
- Tracing evolutionary trajectories of resistance-associated mutations.
- Modeling the impact of mutations on protein structure and stability.
Main Results:
- Drug resistance mutations often destabilize HIV-1 Pol protein structure.
- A general decrease in protein stability is observed across HIV-1's evolutionary history.
- Both drug-resistant and non-drug-resistant mutations (e.g., immune escape) affect protein stability.
Conclusions:
- Protein structure maintenance is a major constraint on HIV-1 evolution.
- Understanding these constraints can inform the development of new antiretroviral strategies.
- Epistatic interactions and protein stability play critical roles in viral adaptation.
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