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Title: Co-Operative Additive Effects between HLA Alleles in Control of HIV-1
Authors: Matthews, Philippa C.;Listgarten, Jennifer;Carlson, Jonathan M.;Payne, Rebecca;Huang, Kuan-Hsiang Gary;Frater, John;Goedhals, Dominique;Steyn, Dewald;van Vuuren, Cloete;Paioni, Paolo;Jooste, Pieter;Ogwu, Anthony;Shapiro, Roger L.;Mncube, Zenele;Ndung'u, Thumbi;Walker, Bruce David;Heckerman, David;Goulder, Philip J. R.
subject: Biology;Immunology;Immune Cells;T Cells;Medicine;Clinical Immunology;Immunity;Adaptive Immunity;Immune Defense;Immune Response;Major Histocompatibility Complex;Infectious Diseases;Viral Diseases;HIV;Retrovirology and HIV immunopathogenesis;Obstetrics and Gynecology;Genitourinary Infections;Urology
Year: 2012
Publisher: Public Library of Science
Description: Background: HLA class I genotype is a major determinant of the outcome of HIV infection, and the impact of certain alleles on HIV disease outcome is well studied. Recent studies have demonstrated that certain HLA class I alleles that are in linkage disequilibrium, such as HLA-A*74 and HLA-B*57, appear to function co-operatively to result in greater immune control of HIV than mediated by either single allele alone. We here investigate the extent to which HLA alleles - irrespective of linkage disequilibrium - function co-operatively. Methodology/Principal Findings: We here refined a computational approach to the analysis of >2000 subjects infected with C-clade HIV first to discern the individual effect of each allele on disease control, and second to identify pairs of alleles that mediate ‘co-operative additive’ effects, either to improve disease suppression or to contribute to immunological failure. We identified six pairs of HLA class I alleles that have a co-operative additive effect in mediating HIV disease control and four hazardous pairs of alleles that, occurring together, are predictive of worse disease outcomes (q<0.05 in each case). We developed a novel ‘sharing score’ to quantify the breadth of CD8+ T cell responses made by pairs of HLA alleles across the HIV proteome, and used this to demonstrate that successful viraemic suppression correlates with breadth of unique CD8+ T cell responses (p = 0.03). Conclusions/Significance: These results identify co-operative effects between HLA Class I alleles in the control of HIV-1 in an extended Southern African cohort, and underline complementarity and breadth of the CD8+ T cell targeting as one potential mechanism for this effect.
Standard no: Matthews, Philippa C., Jennifer Listgarten, Jonathan M. Carlson, Rebecca Payne, Kuan-Hsiang Gary Huang, John Frater, Dominique Goedhals, et al. 2012. Co-operative additive effects between HLA alleles in control of HIV-1. PLoS ONE 7(10): e47799.
Appears in Collections:HSPH Scholarly Articles

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