title: HIV subtype influences HLA-B*07:02-associated HIV disease outcome.
abstract: Genetic polymorphisms within the MHC encoding region have the strongest impact on HIV disease progression of any in the human genome and provide important clues to the mechanisms of HIV immune control. Few analyses have been undertaken of HLA alleles associated with rapid disease progression. HLA-B*07:02 is an HLA class I molecule that is prevalent in most populations worldwide and that has previously been consistently linked to accelerated disease progression in B-clade infection. This study investigates the observation that HLA-B*07:02 is not associated with a high viral setpoint in C-clade infection. We examine the hypothesis that this clade-specific difference in association with disease outcome may be related to distinct targeting of CD8(+) T cell epitopes. We observed that C-clade-infected individuals with HLA-B*07:02 target a broader range of Gag epitopes, and to higher magnitudes, than do individuals infected with B-clade infection. In particular, a novel p17-Gag (Gag22-30, RPGGKKHYM) epitope is targeted in >50% of HLA-B*07:02-positive C-clade-infected individuals but clade-specific differences in this epitope result in nonimmunogenicity in B-clade infection. Only the C-clade p24-Gag "GL9" (Gag355-363, GPSHKARVL) epitope-specific CD8(+) T cell response out of 16 studied was associated with a low viral setpoint. Although this epitope was also targeted in B-clade infection, the escape mutant S357S is present at higher frequency in B-clade infection than in C-clade infection (70% versus 43% in HLA-B*07:02-negative subjects). These data support earlier studies suggesting that increased breadth of the Gag-specific CD8(+) T cell response may contribute to improved HIV immune control irrespective of the particular HLA molecules expressed.
authors.affiliation: 1 Department of Paediatrics, University of Oxford , Oxford, United Kingdom .
authors.forename: Henrik N
authors.initials: HN
authors.lastname: Kløverpris
authors.forename: Emily
authors.initials: E
authors.lastname: Adland
authors.forename: Madoka
authors.initials: M
authors.lastname: Koyanagi
authors.forename: Anette
authors.initials: A
authors.lastname: Stryhn
authors.forename: Mikkel
authors.initials: M
authors.lastname: Harndahl
authors.forename: Philippa C
authors.initials: PC
authors.lastname: Matthews
authors.forename: Roger
authors.initials: R
authors.lastname: Shapiro
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takiguchi
authors.forename: Søren
authors.initials: S
authors.lastname: Buus
authors.forename: Philip
authors.initials: P
authors.lastname: Goulder
mesh_terms: D000328:Adult; D015331:Cohort Studies; D018450:Disease Progression; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005838:Genotype; D015658:HIV Infections / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015793:HLA-B7 Antigen / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D011110:Polymorphism, Genetic; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; C477444:HLA-B*07:02 antigen; D015793:HLA-B7 Antigen; D054301:gag Gene Products, Human Immunodeficiency Virus