Adaptive HIV-1 evolutionary trajectories are constrained by protein stability

Olabode, A. S., Kandathil, S. M., Lovell, S. C. and Robertson, D. L. (2017) Adaptive HIV-1 evolutionary trajectories are constrained by protein stability. Virus Evolution, 3(2), vex019. (doi: 10.1093/ve/vex019) (PMID:28852572) (PMCID:PMC5570062)

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Despite the use of combination antiretroviral drugs for the treatment of HIV-1 infection, the emergence of drug resistance remains a problem. Resistance may be conferred either by a single mutation or a concerted set of mutations. The involvement of multiple mutations can arise due to interactions between sites in the amino acid sequence as a consequence of the need to maintain protein structure. To better understand the nature of such epistatic interactions, we reconstructed the ancestral sequences of HIV-1's Pol protein, and traced the evolutionary trajectories leading to mutations associated with drug resistance. Using contemporary and ancestral sequences we modelled the effects of mutations (i.e. amino acid replacements) on protein structure to understand the functional effects of residue changes. Although the majority of resistance-associated sequences tend to destabilise the protein structure, we find there is a general tendency for protein stability to decrease across HIV-1's evolutionary history. That a similar pattern is observed in the non-drug resistance lineages indicates that non-resistant mutations, for example, associated with escape from the immune response, also impacts on protein stability. Maintenance of optimal protein structure therefore represents a major constraining factor to the evolution of HIV-1.

Item Type:Articles
Keywords:HIV-1, drug resistance, evolution, protein stability, protein structure.
Glasgow Author(s) Enlighten ID:Robertson, Professor David
Authors: Olabode, A. S., Kandathil, S. M., Lovell, S. C., and Robertson, D. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Virus Evolution
Publisher:Oxford University Press
ISSN (Online):2057-1577
Published Online:01 August 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Virus Evolution 3(2): vex019
Publisher Policy:Reproduced under a Creative Commons license

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