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.
Highlights
Intra-host HIV evolution is characterized by very rapid escape from immune responses [1,2,3,4,5]
We develop a phylogenetic model of immune escape and reversion and provide evidence that it outperforms existing models for the detection of selective pressure associated with host immune responses
Instead we expect to see switching between a wild type amino acid associated with high replicative fitness and susceptibility to the immune response, and an escape state with lower fitness
Summary
Intra-host HIV evolution is characterized by very rapid escape from immune responses [1,2,3,4,5]. Such host immune selection pressures are typically mediated by neutralizing antibodies [6], T-helper cells [7] or Cytotoxic T Lymphocytes (CTLs) [1,8,9]. Escape can occur through viral mutations that affect proteosome processing, affinity for transport antigen processing (TAP) proteins, translocation of peptides to the endoplasmic reticulum, antigen processing prior to presentation, binding of MHC class I molecules and recognition by cytotoxic T cells [1]. Much of the work on immune escape from CTL responses in HIV-1 has focused on identifying escape mutations which either prevent MHC binding or recognition by CTLs [1,2,9,19,21,22]
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