PLoS ONE (Jan 2012)

Co-operative additive effects between HLA alleles in control of HIV-1.

  • Philippa C Matthews,
  • Jennifer Listgarten,
  • Jonathan M Carlson,
  • Rebecca Payne,
  • Kuan-Hsiang Gary Huang,
  • John Frater,
  • Dominique Goedhals,
  • Dewald Steyn,
  • Cloete van Vuuren,
  • Paolo Paioni,
  • Pieter Jooste,
  • Anthony Ogwu,
  • Roger Shapiro,
  • Zenele Mncube,
  • Thumbi Ndung'u,
  • Bruce D Walker,
  • David Heckerman,
  • Philip J R Goulder

Journal volume & issue
Vol. 7, no. 10
p. e47799


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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.