title: Fitness costs of mutations at the HIV-1 capsid hexamerization interface.
abstract: 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.
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Siriphan
authors.initials: S
authors.lastname: Manocheewa
authors.forename: J Victor
authors.initials: JV
authors.lastname: Swain
authors.forename: Erinn
authors.initials: E
authors.lastname: Lanxon-Cookson
authors.forename: Morgane
authors.initials: M
authors.lastname: Rolland
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
mesh_terms: D019943:Amino Acid Substitution; D002213:Capsid / Q000737:chemistry*; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D056084:Genetic Fitness; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D055503:Protein Multimerization; D011995:Recombination, Genetic; D014779:Virus Replication
chemical_list: D036022:Capsid Proteins