Additive Contribution of HLA Class I Alleles in the Immune Control of HIV-1 Infection
Por:
Leslie, A, Matthews, PC, Listgarten, J, Carlson, JM, Kadie, C, Ndung'u, T, Brander, C, Coovadia, H, Walker, BD, Heckerman, D and Goulder, PJR
Publicada:
1 oct 2010
Resumen:
Previous studies have identified a central role for HLA-B alleles in influencing control of HIV infection. An alternative possibility is that a small number of HLA-B alleles may have a very strong impact on HIV disease outcome, dominating the contribution of other HLA alleles. Here, we find that even following the exclusion of subjects expressing any of the HLA-B class I alleles (B*57, B*58, and B*18) identified to have the strongest influence on control, the dominant impact of HLA-B alleles on virus set point and absolute CD4 count variation remains significant. However, we also find that the influence of HLA on HIV control in this C-clade-infected cohort from South Africa extends beyond HLA-B as HLA-Cw type remains a significant predictor of virus and CD4 count following exclusion of the strongest HLA-B associations. Furthermore, there is evidence of interdependent protective effects of the HLA-Cw*0401-B*8101, HLA-Cw*1203-B*3910, and HLA-A*7401-B*5703 haplotypes that cannot be explained solely by linkage to a protective HLA-B allele. Analysis of individuals expressing both protective and detrimental alleles shows that even the strongest HLA alleles appear to have an additive rather than dominant effect on HIV control at the individual level. Finally, weak but significant frequency-dependent effects in this cohort can be detected only by looking at an individual's combined HLA allele frequencies. Taken together, these data suggest that although individual HLA alleles, particularly HLA-B, can have a strong impact, HIV control overall is likely to be influenced by the additive effect of some or all of the other HLA alleles present.
Filiaciones:
Leslie, A:
Univ Oxford, Weatherall Inst Mol Med, Oxford OX1 3SY, England
Matthews, PC:
Univ Oxford, Nuffield Dept Med, Dept Paediat, Oxford OX1 3SY, England
Listgarten, J:
Microsoft Res, Machine Learning & Appl Stat Grp, Redmond, WA USA
Carlson, JM:
Microsoft Res, Machine Learning & Appl Stat Grp, Redmond, WA USA
Kadie, C:
Microsoft Res, Machine Learning & Appl Stat Grp, Redmond, WA USA
Ndung'u, T:
Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa
:
Hosp Badalona Germans Trias & Pujol, Fundacio IrsiCaixa HIVACAT, Badalona, Spain
Inst Catalana Recerca & Estudis Avancats, Barcelona 08916, Spain
Coovadia, H:
Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa
Walker, BD:
Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa
Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ragon Inst, Boston, MA USA
Howard Hughes Med Inst, Chevy Chase, MD USA
Heckerman, D:
Microsoft Res, Machine Learning & Appl Stat Grp, Redmond, WA USA
Goulder, PJR:
Univ Oxford, Nuffield Dept Med, Dept Paediat, Oxford OX1 3SY, England
Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa
Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ragon Inst, Boston, MA USA
Green Published
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