title: HLA-A*7401-mediated control of HIV viremia is independent of its linkage disequilibrium with HLA-B*5703.
abstract: The potential contribution of HLA-A alleles to viremic control in chronic HIV type 1 (HIV-1) infection has been relatively understudied compared with HLA-B. In these studies, we show that HLA-A*7401 is associated with favorable viremic control in extended southern African cohorts of >2100 C-clade-infected subjects. We present evidence that HLA-A*7401 operates an effect that is independent of HLA-B*5703, with which it is in linkage disequilibrium in some populations, to mediate lowered viremia. We describe a novel statistical approach to detecting additive effects between class I alleles in control of HIV-1 disease, highlighting improved viremic control in subjects with HLA-A*7401 combined with HLA-B*57. In common with HLA-B alleles that are associated with effective control of viremia, HLA-A*7401 presents highly targeted epitopes in several proteins, including Gag, Pol, Rev, and Nef, of which the Gag epitopes appear immunodominant. We identify eight novel putative HLA-A*7401-restricted epitopes, of which three have been defined to the optimal epitope. In common with HLA-B alleles linked with slow progression, viremic control through an HLA-A*7401-restricted response appears to be associated with the selection of escape mutants within Gag epitopes that reduce viral replicative capacity. These studies highlight the potentially important contribution of an HLA-A allele to immune control of HIV infection, which may have been concealed by a stronger effect mediated by an HLA-B allele with which it is in linkage disequilibrium. In addition, these studies identify a factor contributing to different HIV disease outcomes in individuals expressing HLA-B*5703.
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom.
authors.forename: Philippa C
authors.initials: PC
authors.lastname: Matthews
authors.forename: Emily
authors.initials: E
authors.lastname: Adland
authors.forename: Jennifer
authors.initials: J
authors.lastname: Listgarten
authors.forename: Alasdair
authors.initials: A
authors.lastname: Leslie
authors.forename: Nompumelelo
authors.initials: N
authors.lastname: Mkhwanazi
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.forename: Mikkel
authors.initials: M
authors.lastname: Harndahl
authors.forename: Anette
authors.initials: A
authors.lastname: Stryhn
authors.forename: Rebecca P
authors.initials: RP
authors.lastname: Payne
authors.forename: Anthony
authors.initials: A
authors.lastname: Ogwu
authors.forename: Kuan-Hsiang Gary
authors.initials: KH
authors.lastname: Huang
authors.forename: John
authors.initials: J
authors.lastname: Frater
authors.forename: Paolo
authors.initials: P
authors.lastname: Paioni
authors.forename: Henrik
authors.initials: H
authors.lastname: Kloverpris
authors.forename: Pieter
authors.initials: P
authors.lastname: Jooste
authors.forename: Dominique
authors.initials: D
authors.lastname: Goedhals
authors.forename: Cloete
authors.initials: C
authors.lastname: van Vuuren
authors.forename: Dewald
authors.initials: D
authors.lastname: Steyn
authors.forename: Lynn
authors.initials: L
authors.lastname: Riddell
authors.forename: Fabian
authors.initials: F
authors.lastname: Chen
authors.forename: Graz
authors.initials: G
authors.lastname: Luzzi
authors.forename: Thambiah
authors.initials: T
authors.lastname: Balachandran
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.forename: Søren
authors.initials: S
authors.lastname: Buus
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.forename: Roger
authors.initials: R
authors.lastname: Shapiro
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
mesh_terms: D000349:Africa; D000483:Alleles; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015234:HLA-A Antigens / Q000235:genetics* / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D020539:Sequence Analysis, Protein; D019562:Viral Load; D014766:Viremia / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000276:immunology; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000276:immunology; D054321:rev Gene Products, Human Immunodeficiency Virus / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D015235:HLA-B Antigens; C496219:HLA-B*57:03 antigen; D054301:gag Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D054302:pol Gene Products, Human Immunodeficiency Virus; D054321:rev Gene Products, Human Immunodeficiency Virus; C514860:rev protein, Human Immunodeficiency Virus-1