title: Evolution of HLA-B*5703 HIV-1 escape mutations in HLA-B*5703-positive individuals and their transmission recipients.
abstract: HLA-B*57 is the class I allele most consistently associated with control of human immunodeficiency virus (HIV) replication, which may be linked to the specific HIV peptides that this allele presents to cytotoxic T lymphocytes (CTLs), and the resulting efficacy of these cellular immune responses. In two HIV C clade-infected populations in South Africa and Zambia, we sought to elucidate the role of HLA-B*5703 in HIV disease outcome. HLA-B*5703-restricted CTL responses select for escape mutations in three Gag p24 epitopes, in a predictable order. We show that the accumulation of these mutations sequentially reduces viral replicative capacity in vitro. Despite this, in vivo data demonstrate that there is ultimately an increase in viral load concomitant with evasion of all three HLA-B*5703-restricted CTL responses. In HLA-B*5703-mismatched recipients, the previously described early benefit of transmitted HLA-B*5703-associated escape mutations is abrogated by the increase in viral load coincident with reversion. Rapid disease progression is observed in HLA-matched recipients to whom mutated virus is transmitted. These data demonstrate that, although costly escape from CTL responses can progressively attenuate the virus, high viral loads develop in the absence of adequate, continued CTL responses. These data underline the need for a CTL vaccine against multiple conserved epitopes.
authors.affiliation: Department of Pediatrics, University of Oxford, England, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Crawford
authors.forename: Wendy
authors.initials: W
authors.lastname: Lumm
authors.forename: Alasdair
authors.initials: A
authors.lastname: Leslie
authors.forename: Malinda
authors.initials: M
authors.lastname: Schaefer
authors.forename: Debrah
authors.initials: D
authors.lastname: Boeras
authors.forename: Julia G
authors.initials: JG
authors.lastname: Prado
authors.forename: Jianming
authors.initials: J
authors.lastname: Tang
authors.forename: Paul
authors.initials: P
authors.lastname: Farmer
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.forename: Shabir
authors.initials: S
authors.lastname: Lakhi
authors.forename: Jill
authors.initials: J
authors.lastname: Gilmour
authors.forename: Paul
authors.initials: P
authors.lastname: Goepfert
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Richard
authors.initials: R
authors.lastname: Kaslow
authors.forename: Joseph
authors.initials: J
authors.lastname: Mulenga
authors.forename: Susan
authors.initials: S
authors.lastname: Allen
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
authors.forename: Eric
authors.initials: E
authors.lastname: Hunter
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology*; D000595:Amino Acid Sequence; D017124:Conserved Sequence; D018450:Disease Progression; D000939:Epitopes / Q000235:genetics; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology; D016655:HIV Core Protein p24 / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics*; D006801:Humans; D009154:Mutation; D011110:Polymorphism, Genetic; D013019:South Africa; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D016896:Treatment Outcome; D015024:Zambia
chemical_list: D000939:Epitopes; D015683:Gene Products, gag; D016655:HIV Core Protein p24; D015235:HLA-B Antigens; C496219:HLA-B*57:03 antigen