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
PLoS ONE | , pp. e47799
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.