TY - JOUR

T1 - Differential immunodominance hierarchy of CD8+ T-cell responses in HLA-B*27

T2 - 05- and -B*27:02-mediated control of HIV-1 infection

AU - Adland, Emily

AU - Hill, Matilda

AU - Lavandier, Nora

AU - Csala, Anna

AU - Edwards, Anne

AU - Chen, Fabian

AU - Radkowski, Marek

AU - Kowalska, Justyna D.

AU - Paraskevis, Dimitrios

AU - Hatzakis, Angelos

AU - Valenzuela-Ponce, Humberto

AU - Pfafferott, Katja

AU - Williams, Ian

AU - Pellegrino, Pierre

AU - Borrow, Persephone

AU - Mori, Masahiko

AU - Rockstroh, Jürgen

AU - Prado, Julia G.

AU - Mothe, Beatriz

AU - Dalmau, Judith

AU - Martinez-Picado, Javier

AU - Tudor-Williams, Gareth

AU - Frater, John

AU - Stryhn, Anette

AU - Buus, Soren

AU - Teran, Gustavo Reyes

AU - Mallal, Simon

AU - John, Mina

AU - Buchbinder, Susan

AU - Kirk, Gregory

AU - Martin, Jeffrey

AU - Michael, Nelson

AU - Fellay, Jacques

AU - Deeks, Steve

AU - Walker, Bruce

AU - Avila-Rios, Santiago

AU - Cole, David

AU - Brander, Christian

AU - Carrington, Mary

AU - Goulder, Philip

PY - 2018/2

Y1 - 2018/2

N2 - The well-characterized association between HLA-B*27:05 and protection against HIV disease progression has been linked to immunodominant HLA-B*27:05- restricted CD8+ T-cell responses toward the conserved Gag KK10 (residues 263 to 272) and polymerase (Pol) KY9 (residues 901 to 909) epitopes. We studied the impact of the 3 amino acid differences between HLA-B*27:05 and the closely related HLA-B*27:02 on the HIV-specific CD8+ T-cell response hierarchy and on immune control of HIV. Genetic epidemiological data indicate that both HLA-B*27:02 and HLA-B*27:05 are associated with slower disease progression and lower viral loads. The effect of HLA-B*27:02 appeared to be consistently stronger than that of HLAB* 27:05. In contrast to HLA-B*27:05, the immunodominant HIV-specific HLA-B*27:02- restricted CD8+ T-cell response is to a Nef epitope (residues 142 to 150 [VW9]), with Pol KY9 subdominant and Gag KK10 further subdominant. This selection was driven by structural differences in the F pocket, mediated by a polymorphism between these two HLA alleles at position 81. Analysis of autologous virus sequences showed that in HLA-B*27:02-positive subjects, all three of these CD8+ T-cell responses impose selection pressure on the virus, whereas in HLA-B*27:05-positive subjects, there is no Nef VW9-mediated selection pressure. These studies demonstrate that HLAB* 27:02 mediates protection against HIV disease progression that is at least as strong as or stronger than that mediated by HLA-B*27:05. In combination with the protective Gag KK10 and Pol KY9 CD8+ T-cell responses that dominate HIV-specific CD8+ T-cell activity in HLA-B*27:05-positive subjects, a Nef VW9-specific response is additionally present and immunodominant in HLA-B*27:02-positive subjects, mediated through a polymorphism at residue 81 in the F pocket, that contributes to selection pressure against HIV.

AB - The well-characterized association between HLA-B*27:05 and protection against HIV disease progression has been linked to immunodominant HLA-B*27:05- restricted CD8+ T-cell responses toward the conserved Gag KK10 (residues 263 to 272) and polymerase (Pol) KY9 (residues 901 to 909) epitopes. We studied the impact of the 3 amino acid differences between HLA-B*27:05 and the closely related HLA-B*27:02 on the HIV-specific CD8+ T-cell response hierarchy and on immune control of HIV. Genetic epidemiological data indicate that both HLA-B*27:02 and HLA-B*27:05 are associated with slower disease progression and lower viral loads. The effect of HLA-B*27:02 appeared to be consistently stronger than that of HLAB* 27:05. In contrast to HLA-B*27:05, the immunodominant HIV-specific HLA-B*27:02- restricted CD8+ T-cell response is to a Nef epitope (residues 142 to 150 [VW9]), with Pol KY9 subdominant and Gag KK10 further subdominant. This selection was driven by structural differences in the F pocket, mediated by a polymorphism between these two HLA alleles at position 81. Analysis of autologous virus sequences showed that in HLA-B*27:02-positive subjects, all three of these CD8+ T-cell responses impose selection pressure on the virus, whereas in HLA-B*27:05-positive subjects, there is no Nef VW9-mediated selection pressure. These studies demonstrate that HLAB* 27:02 mediates protection against HIV disease progression that is at least as strong as or stronger than that mediated by HLA-B*27:05. In combination with the protective Gag KK10 and Pol KY9 CD8+ T-cell responses that dominate HIV-specific CD8+ T-cell activity in HLA-B*27:05-positive subjects, a Nef VW9-specific response is additionally present and immunodominant in HLA-B*27:02-positive subjects, mediated through a polymorphism at residue 81 in the F pocket, that contributes to selection pressure against HIV.

KW - CD8 T cell

KW - HIV Gag

KW - HIV Nef

KW - HLA

KW - HLA-B27

KW - Human immunodeficiency virus

U2 - 10.1128/JVI.01685-17

DO - 10.1128/JVI.01685-17

M3 - Journal article

C2 - 29167337

AN - SCOPUS:85041231839

VL - 92

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 4

M1 - e01685-17

ER -