Frequent toggling between alternative amino acids is driven by selection in HIV-1

PLoS Pathog. 2008 Dec;4(12):e1000242. doi: 10.1371/journal.ppat.1000242. Epub 2008 Dec 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acids / genetics*
  • Amino Acids / immunology*
  • Amino Acids / metabolism
  • Antigens, Surface / genetics
  • Antigens, Surface / metabolism
  • Codon / genetics
  • Computer Simulation
  • HIV Antigens / genetics
  • HIV Antigens / immunology
  • HIV Antigens / metabolism
  • HIV Infections / genetics
  • HIV Infections / immunology
  • HIV-1 / genetics*
  • HIV-1 / immunology
  • HIV-1 / metabolism
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology
  • Humans
  • Immune Tolerance / genetics
  • Models, Genetic
  • Models, Theoretical
  • Molecular Sequence Data
  • Phylogeny
  • Polymorphism, Genetic / immunology
  • Polymorphism, Genetic / physiology
  • Selection, Genetic*


  • Amino Acids
  • Antigens, Surface
  • Codon
  • HIV Antigens
  • Histocompatibility Antigens Class I