title: HLA footprints on human immunodeficiency virus type 1 are associated with interclade polymorphisms and intraclade phylogenetic clustering.
abstract: The selection of escape mutations has a major impact on immune control of infections with viruses such as human immunodeficiency virus (HIV). Viral evasion of CD8(+) T-cell responses leaves predictable combinations of escape mutations, termed HLA "footprints." The most clearly defined footprints are those associated with HLA alleles that are linked with successful control of HIV, such as HLA-B*57. Here we investigated the extent to which HLA footprint sites in HIV type 1 (HIV-1) are associated with viral evolution among and within clades. First, we examined the extent to which amino acid differences between HIV-1 clades share identity with sites of HLA-mediated selection pressure and observed a strong association, in particular with respect to sites of HLA-B selection (P < 10(-6)). Similarly, the sites of amino acid variability within a clade were found to overlap with sites of HLA-selected mutation. Second, we studied the impact of HLA selection on interclade phylogeny. Removing the sites of amino acid variability did not significantly affect clade-specific clustering, reflecting the central role of founder effects in establishing distinct clades. However, HLA footprints may underpin founder strains, and we show that amino acid substitutions between clades alter phylogeny, underlining a potentially substantial role for HLA in driving ongoing viral evolution. Finally, we investigated the impact of HLA selection on within-clade phylogeny and demonstrate that even a single HLA allele footprint can result in significant phylogenetic clustering of sequences. In conclusion, these data highlight the fact that HLA can be a strong selection force for both intra- and interclade HIV evolution at a population level.
authors.affiliation: Department of Paediatrics, Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, Oxford, United Kingdom. p.matthews@doctors.org.uk
authors.forename: Philippa C
authors.initials: PC
authors.lastname: Matthews
authors.forename: Alasdair J
authors.initials: AJ
authors.lastname: Leslie
authors.forename: Aris
authors.initials: A
authors.lastname: Katzourakis
authors.forename: Hayley
authors.initials: H
authors.lastname: Crawford
authors.forename: Rebecca
authors.initials: R
authors.lastname: Payne
authors.forename: Andrew
authors.initials: A
authors.lastname: Prendergast
authors.forename: Karen
authors.initials: K
authors.lastname: Power
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Kelleher
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.forename: Jonathan
authors.initials: J
authors.lastname: Carlson
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Pybus
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
mesh_terms: D000595:Amino Acid Sequence; D016384:Consensus Sequence; D015683:Gene Products, gag / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D006680:HLA Antigens / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics* / Q000276:immunology; D009154:Mutation / Q000235:genetics; D010802:Phylogeny; D011110:Polymorphism, Genetic / Q000235:genetics* / Q000276:immunology; D016415:Sequence Alignment
chemical_list: D015683:Gene Products, gag; D006680:HLA Antigens