Frequent toggling between alternative amino acids Is driven by selection in HIV-1
Date
2008
Journal Title
Journal ISSN
Volume Title
Publisher
Public Library of Science
Abstract
Host immune responses against infectious pathogens exert strong selective pressures favouring the emergence of escape
mutations that prevent immune recognition. Escape mutations within or flanking functionally conserved epitopes can occur
at a significant cost to the pathogen in terms of its ability to replicate effectively. Such mutations come under selective
pressure to revert to the wild type in hosts that do not mount an immune response against the epitope. Amino acid
positions exhibiting this pattern of escape and reversion are of interest because they tend to coincide with immune
responses that control pathogen replication effectively. We have used a probabilistic model of protein coding sequence
evolution to detect sites in HIV-1 exhibiting a pattern of rapid escape and reversion. Our model is designed to detect sites
that toggle between a wild type amino acid, which is susceptible to a specific immune response, and amino acids with
lower replicative fitness that evade immune recognition. Through simulation, we show that this model has significantly
greater power to detect selection involving immune escape and reversion than standard models of diversifying selection,
which are sensitive to an overall increased rate of non-synonymous substitution. Applied to alignments of HIV-1 protein
coding sequences, the model of immune escape and reversion detects a significantly greater number of adaptively evolving
sites in env and nef. In all genes tested, the model provides a significantly better description of adaptively evolving sites than
standard models of diversifying selection. Several of the sites detected are corroborated by association between Human
Leukocyte Antigen (HLA) and viral sequence polymorphisms. Overall, there is evidence for a large number of sites in HIV-1
evolving under strong selective pressure, but exhibiting low sequence diversity. A phylogenetic model designed to detect
rapid toggling between wild type and escape amino acids identifies a larger number of adaptively evolving sites in HIV-1,
and can in some cases correctly identify the amino acid that is susceptible to the immune response.
Description
CITATION: Delport, W., Scheffler, K. & Seoighe, C. 2008. Frequent toggling between alternative amino acids Is driven by Selection in HIV-1. PLoS Pathogens, 4(12): 1-13, doi: 10.1371/journal.ppat.1000242.
The original publication is available at http://journals.plos.org/plospathogens
The original publication is available at http://journals.plos.org/plospathogens
Keywords
HIV (Viruses) -- Research, Amino acids -- Research -- Mathematical models, Immune response -- Molecular aspects, Viruses -- Variation -- Mathematical models, Molecular biology -- Research -- Mathematical models
Citation
Delport, W., Scheffler, K. & Seoighe, C. 2008. Frequent toggling between alternative amino acids Is driven by Selection in HIV-1. PLoS Pathogens, 4(12): 1-13, doi: 10.1371/journal.ppat.1000242