title: Transmission and accumulation of CTL escape variants drive negative associations between HIV polymorphisms and HLA.
abstract: Human immunodeficiency virus (HIV)-1 amino acid sequence polymorphisms associated with expression of specific human histocompatibility leukocyte antigen (HLA) class I alleles suggest sites of cytotoxic T lymphocyte (CTL)-mediated selection pressure and immune escape. The associations most frequently observed are between expression of an HLA class I molecule and variation from the consensus sequence. However, a substantial number of sites have been identified in which particular HLA class I allele expression is associated with preservation of the consensus sequence. The mechanism behind this is so far unexplained. The current studies, focusing on two examples of "negatively associated" or apparently preserved epitopes, suggest an explanation for this phenomenon: negative associations can arise as a result of positive selection of an escape mutation, which is stable on transmission and therefore accumulates in the population to the point at which it defines the consensus sequence. Such negative associations may only be in evidence transiently, because the statistical power to detect them diminishes as the mutations accumulate. If an escape variant reaches fixation in the population, the epitope will be lost as a potential target to the immune system. These data help to explain how HIV is evolving at a population level. Understanding the direction of HIV evolution has important implications for vaccine development.
authors.affiliation: Peter Medawar Building, University of Oxford, Oxford OX13SY, UK.
authors.forename: Alasdair
authors.initials: A
authors.lastname: Leslie
authors.forename: Daniel
authors.initials: D
authors.lastname: Kavanagh
authors.forename: Isobella
authors.initials: I
authors.lastname: Honeyborne
authors.forename: Katja
authors.initials: K
authors.lastname: Pfafferott
authors.forename: Charles
authors.initials: C
authors.lastname: Edwards
authors.forename: Tilly
authors.initials: T
authors.lastname: Pillay
authors.forename: Louise
authors.initials: L
authors.lastname: Hilton
authors.forename: Christina
authors.initials: C
authors.lastname: Thobakgale
authors.forename: Danni
authors.initials: D
authors.lastname: Ramduth
authors.forename: Rika
authors.initials: R
authors.lastname: Draenert
authors.forename: Sylvie
authors.initials: S
authors.lastname: Le Gall
authors.forename: Graz
authors.initials: G
authors.lastname: Luzzi
authors.forename: Anne
authors.initials: A
authors.lastname: Edwards
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.forename: Sarah
authors.initials: S
authors.lastname: Moore
authors.forename: James
authors.initials: J
authors.lastname: Mullins
authors.forename: Corey
authors.initials: C
authors.lastname: Moore
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
authors.forename: Karina
authors.initials: K
authors.lastname: Yusim
authors.forename: Rodney
authors.initials: R
authors.lastname: Phillips
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.forename: Bette
authors.initials: B
authors.lastname: Korber
authors.forename: Photini
authors.initials: P
authors.lastname: Kiepiela
authors.forename: Bruce
authors.initials: B
authors.lastname: Walker
authors.forename: Philip
authors.initials: P
authors.lastname: Goulder
mesh_terms: D016915:AIDS Vaccines; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D016384:Consensus Sequence / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D019143:Evolution, Molecular; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000635:transmission*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics / Q000276:immunology; D011110:Polymorphism, Genetic / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens