title: Amino-acid co-variation in HIV-1 Gag subtype C: HLA-mediated selection pressure and compensatory dynamics.
abstract: BACKGROUND
  Despite high potential for HIV-1 genetic variation, the emergence of some mutations is constrained by fitness costs, and may be associated with compensatory amino acid (AA) co-variation. To characterize the interplay between Cytotoxic T Lymphocyte (CTL)-mediated pressure and HIV-1 evolutionary pathways, we investigated AA co-variation in Gag sequences obtained from 449 South African individuals chronically infected with HIV-1 subtype C.
  
  
  RESULTS
  Individuals with CTL responses biased toward Gag presented lower viral loads than individuals with under-represented Gag-specific CTL responses. Using methods that account for founder effects and HLA linkage disequilibrium, we identified 35 AA sites under Human Leukocyte Antigen (HLA)-restricted CTL selection pressure and 534 AA-to-AA interactions. Analysis of two-dimensional distances between co-varying residues revealed local stabilization mechanisms since 40% of associations involved neighboring residues. Key features of our co-variation analysis included sites with a high number of co-varying partners, such as HLA-associated sites, which had on average 55% more connections than other co-varying sites.
  
  
  CONCLUSIONS
  Clusters of co-varying AA around HLA-associated sites (especially at typically conserved sites) suggested that cooperative interactions act to preserve the local structural stability and protein function when CTL escape mutations occur. These results expose HLA-imprinted HIV-1 polymorphisms and their interlinked mutational paths in Gag that are likely due to opposite selective pressures from host CTL-mediated responses and viral fitness constraints.
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America. mrolland@u.washington.edu
authors.forename: Morgane
authors.initials: M
authors.lastname: Rolland
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
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: Wenjie
authors.initials: W
authors.lastname: Deng
authors.forename: Christine M
authors.initials: CM
authors.lastname: Rousseau
authors.forename: Dana N
authors.initials: DN
authors.lastname: Raugi
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Learn
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Maust
authors.forename: Hoosen
authors.initials: H
authors.lastname: Coovadia
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: David E
authors.initials: DE
authors.lastname: Heckerman
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
mesh_terms: D000595:Amino Acid Sequence; D044383:Black People / Q000235:genetics; D002460:Cell Line; D015331:Cohort Studies; D014644:Genetic Variation; D015658:HIV Infections / Q000235:genetics* / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011110:Polymorphism, Genetic; D012641:Selection, Genetic; D013019:South Africa; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D006680:HLA Antigens; D054301:gag Gene Products, Human Immunodeficiency Virus
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