Fitness costs of mutations at the HIV-1 capsid hexamerization interface

PLoS One. 2013 Jun 13;8(6):e66065. doi: 10.1371/journal.pone.0066065. Print 2013.


The recently available x-ray crystal structure of HIV-1 capsid hexamers has provided insight into the molecular interactions crucial for the virus's mature capsid formation. Amino acid changes at these interaction points are likely to have a strong impact on capsid functionality and, hence, viral infectivity and replication fitness. To test this hypothesis, we introduced the most frequently observed single amino acid substitution at 30 sites: 12 at the capsid hexamerization interface and 18 at non-interface sites. Mutations at the interface sites were more likely to be lethal (Fisher's exact test p = 0.027) and had greater negative impact on viral replication fitness (Wilcoxon rank sum test p = 0.040). Among the interface mutations studied, those located in the cluster of hydrophobic contacts at NTD-NTD interface and those that disrupted NTD-CTD inter-domain helix capping hydrogen bonds were the most detrimental, indicating that these interactions are particularly important for maintaining capsid structure and/or function. These functionally constrained sites provide potential targets for novel HIV drug development and vaccine immunogen design.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Substitution
  • Capsid / chemistry*
  • Capsid Proteins / chemistry
  • Capsid Proteins / genetics*
  • Capsid Proteins / metabolism*
  • Cell Line
  • Genetic Fitness*
  • HIV-1 / genetics*
  • HIV-1 / metabolism*
  • HIV-1 / physiology
  • Humans
  • Models, Molecular
  • Mutation*
  • Protein Conformation
  • Protein Multimerization*
  • Recombination, Genetic
  • Virus Replication


  • Capsid Proteins