title: Differential clade-specific HLA-B*3501 association with HIV-1 disease outcome is linked to immunogenicity of a single Gag epitope.
abstract: The strongest genetic influence on immune control in HIV-1 infection is the HLA class I genotype. Rapid disease progression in B-clade infection has been linked to HLA-B*35 expression, in particular to the less common HLA-B*3502 and HLA-B*3503 subtypes but also to the most prevalent subtype, HLA-B*3501. In these studies we first demonstrated that whereas HLA-B*3501 is associated with a high viral set point in two further B-clade-infected cohorts, in Japan and Mexico, this association does not hold in two large C-clade-infected African cohorts. We tested the hypothesis that clade-specific differences in HLA associations with disease outcomes may be related to distinct targeting of critical CD8(+) T-cell epitopes. We observed that only one epitope was significantly targeted differentially, namely, the Gag-specific epitope NPPIPVGDIY (NY10, Gag positions 253 to 262) (P = 2 × 10(-5)). In common with two other HLA-B*3501-restricted epitopes, in Gag and Nef, that were not targeted differentially, a response toward NY10 was associated with a significantly lower viral set point. Nonimmunogenicity of NY10 in B-clade-infected subjects derives from the Gag-D260E polymorphism present in ∼90% of B-clade sequences, which critically reduces recognition of the Gag NY10 epitope. These data suggest that in spite of any inherent HLA-linked T-cell receptor repertoire differences that may exist, maximizing the breadth of the Gag-specific CD8(+) T-cell response, by the addition of even a single epitope, may be of overriding importance in achieving immune control of HIV infection. This distinction is of direct relevance to development of vaccines designed to optimize the anti-HIV CD8(+) T-cell response in all individuals, irrespective of HLA type.
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
authors.forename: Philippa C
authors.initials: PC
authors.lastname: Matthews
authors.forename: Madoka
authors.initials: M
authors.lastname: Koyanagi
authors.forename: Henrik N
authors.initials: HN
authors.lastname: Kløverpris
authors.forename: Mikkel
authors.initials: M
authors.lastname: Harndahl
authors.forename: Anette
authors.initials: A
authors.lastname: Stryhn
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Akahoshi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
authors.forename: Claudia
authors.initials: C
authors.lastname: Juarez Molina
authors.forename: Humberto
authors.initials: H
authors.lastname: Valenzuela Ponce
authors.forename: Santiago
authors.initials: S
authors.lastname: Avila Rios
authors.forename: David
authors.initials: D
authors.lastname: Cole
authors.forename: Jonathan
authors.initials: J
authors.lastname: Carlson
authors.forename: Rebecca P
authors.initials: RP
authors.lastname: Payne
authors.forename: Anthony
authors.initials: A
authors.lastname: Ogwu
authors.forename: Alfred
authors.initials: A
authors.lastname: Bere
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.forename: Kamini
authors.initials: K
authors.lastname: Gounder
authors.forename: Fabian
authors.initials: F
authors.lastname: Chen
authors.forename: Lynn
authors.initials: L
authors.lastname: Riddell
authors.forename: Graz
authors.initials: G
authors.lastname: Luzzi
authors.forename: Roger
authors.initials: R
authors.lastname: Shapiro
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Bruce
authors.initials: B
authors.lastname: Walker
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.forename: Gustavo
authors.initials: G
authors.lastname: Reyes Teran
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Eric
authors.initials: E
authors.lastname: Hunter
authors.forename: Søren
authors.initials: S
authors.lastname: Buus
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takiguchi
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
mesh_terms: D000353:Africa, Southern; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018450:Disease Progression; D058501:Enzyme-Linked Immunospot Assay; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D005434:Flow Cytometry; D015683:Gene Products, gag / Q000235:genetics* / Q000276:immunology; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology*; D015497:HIV-1; D015797:HLA-B35 Antigen / Q000145:classification / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007564:Japan; D008800:Mexico; D010802:Phylogeny; D006113:United Kingdom; D019562:Viral Load
chemical_list: D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; C500431:HLA-B*35:01 antigen; D015797:HLA-B35 Antigen