title: The hypervariable HIV-1 capsid protein residues comprise HLA-driven CD8+ T-cell escape mutations and covarying HLA-independent polymorphisms.
abstract: One proposed HIV vaccine strategy is to induce Gag-specific CD8(+) T-cell responses that can corner the virus, through fitness cost of viral escape and unavailability of compensatory mutations. We show here that the most variable capsid residues principally comprise escape mutants driven by protective alleles HLA-B*57, -5801, and -8101 and covarying HLA-independent polymorphisms that arise in conjunction with these escape mutations. These covarying polymorphisms are potentially compensatory and are concentrated around three tropism-determining loops of p24, suggesting structural interdependencies. Our results demonstrate complex patterns of adaptation of HIV under immune selection pressure, the understanding of which should aid vaccine design.
authors.affiliation: Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, South Parks Rd, Oxford OX1 3SY, United Kingdom.
authors.forename: Hayley
authors.initials: H
authors.lastname: Crawford
authors.forename: Philippa C
authors.initials: PC
authors.lastname: Matthews
authors.forename: Malinda
authors.initials: M
authors.lastname: Schaefer
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.forename: Alasdair
authors.initials: A
authors.lastname: Leslie
authors.forename: William
authors.initials: W
authors.lastname: Kilembe
authors.forename: Susan
authors.initials: S
authors.lastname: Allen
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Eric
authors.initials: E
authors.lastname: Hunter
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004252:DNA Mutational Analysis; D016655:HIV Core Protein p24 / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D008958:Models, Molecular; D020125:Mutation, Missense; D011110:Polymorphism, Genetic
chemical_list: D016655:HIV Core Protein p24; D006680:HLA Antigens; C514799:p24 protein, Human Immunodeficiency Virus Type 1