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J Virol ; 86(23): 12643-54, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22973023

RESUMO

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.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/genética , Produtos do Gene gag/genética , Infecções por HIV/genética , Infecções por HIV/imunologia , HIV-1 , Antígeno HLA-B35/genética , África Austral , Progressão da Doença , ELISPOT , Epitopos de Linfócito T/imunologia , Citometria de Fluxo , Produtos do Gene gag/imunologia , Antígeno HLA-B35/classificação , Antígeno HLA-B35/imunologia , Humanos , Japão , México , Filogenia , Reino Unido , Carga Viral
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