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ABSTRACT 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 HLA-B*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 HLA-B*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. IMPORTANCE: CD8+ T cells play a central role in successful control of HIV infection and have the potential also to mediate the eradication of viral reservoirs of infection. The principal means by which protective HLA class I molecules, such as HLA-B*27:05 and HLA-B*57:01, slow HIV disease progression is believed to be via the particular HIV-specific CD8+ T cell responses restricted by those alleles. We focus here on HLA-B*27:05, one of the best-characterized protective HLA molecules, and the closely related HLA-B*27:02, which differs by only 3 amino acids and which has not been well studied in relation to control of HIV infection. We show that HLA-B*27:02 is also protective against HIV disease progression, but the CD8+ T-cell immunodominance hierarchy of HLA-B*27:02 differs strikingly from that of HLA-B*27:05. These findings indicate that the immunodominant HLA-B*27:02-restricted Nef response adds to protection mediated by the Gag and Pol specificities that dominate anti-HIV CD8+ T-cell activity in HLA-B*27:05-positive subjects.

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Autor(es)

Adland, Emily -  Hill, Matilda -  Lavandier, Nora -  Csala, Anna -  Edwards, Anne -  Chen, Fabian -  Radkowski, Marek -  Kowalska, Justyna D. -  Paraskevis, Dimitrios -  Hatzakis, Angelos -  Valenzuela -  Ponce, Humberto -  Pfafferott, Katja -  Williams, Ian -  Pellegrino, Pierre -  Borrow, Persephone -  Mori, Masahiko -  Rockstroh, Jürgen -  Prado, Julia G. -  Mothe, Beatriz -  Dalmau, Judith -  Martinez -  Picado, Javier -  Tudor -  Williams, Gareth -  Frater, John -  Stryhn, Anette -  Buus, Soren -  Teran, Gustavo Reyes -  Mallal, Simon -  John, Mina -  Buchbinder, Susan -  Kirk, Gregory -  Martin, Jeffrey -  Michael, Nelson -  Fellay, Jacques -  Deeks, Steve -  Walker, Bruce -  Avila -  Rios, Santiago -  Cole, David -  Brander, Christian -  Carrington, Mary -  Goulder, Philip - 

Id.: 71110114

Idioma: inglés (Estados Unidos)  - 

Versión: 1.0

Estado: Final

Palabras claveCD8 - 

Tipo de recurso: Journal Article  - 

Tipo de Interactividad: Expositivo

Nivel de Interactividad: muy bajo

Audiencia: Estudiante  -  Profesor  -  Autor  - 

Estructura: Atomic

Coste: no

Copyright: sí

: open

Requerimientos técnicos:  Browser: Any - 

Relación: [References] doi:10.1128/JVI.01685-17
[References] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790925/pdf/
[References] Journal of Virology

Fecha de contribución: 22-mar-2018

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