%0 Journal Article
%T Co-Operative Additive Effects between HLA Alleles in Control of HIV-1
%A Philippa C. Matthews
%A Jennifer Listgarten
%A Jonathan M. Carlson
%A Rebecca Payne
%A Kuan-Hsiang Gary Huang
%A John Frater
%A Dominique Goedhals
%A Dewald Steyn
%A Cloete van Vuuren
%A Paolo Paioni
%A Pieter Jooste
%A Anthony Ogwu
%A Roger Shapiro
%A Zenele Mncube
%A Thumbi Ndung'u
%A Bruce D. Walker
%A David Heckerman
%A Philip J. R. Goulder
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0047799
%X 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.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0047799