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Adaptive HIV-1 evolutionary trajectories are constrained by protein stability

Olabode, AS; Kandathil, SM; Lovell, SC; Robertson, DL; (2017) Adaptive HIV-1 evolutionary trajectories are constrained by protein stability. Virus Evolution , 3 (2) , Article vex019. 10.1093/ve/vex019. Green open access

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Abstract

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.

Type: Article
Title: Adaptive HIV-1 evolutionary trajectories are constrained by protein stability
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/ve/vex019
Publisher version: http://dx.doi.org/10.1093/ve/vex019
Language: English
Additional information: VC The Author 2017. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: HIV-1; evolution; drug resistance; protein structure; protein stability.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Computer Science
URI: http://discovery.ucl.ac.uk/id/eprint/10045337
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