title: Co-operative additive effects between HLA alleles in control of HIV-1.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford, United Kingdom. p.matthews@doctors.org.uk
authors.forename: Philippa C
authors.initials: PC
authors.lastname: Matthews
authors.forename: Jennifer
authors.initials: J
authors.lastname: Listgarten
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.forename: Rebecca
authors.initials: R
authors.lastname: Payne
authors.forename: Kuan-Hsiang Gary
authors.initials: KH
authors.lastname: Huang
authors.forename: John
authors.initials: J
authors.lastname: Frater
authors.forename: Dominique
authors.initials: D
authors.lastname: Goedhals
authors.forename: Dewald
authors.initials: D
authors.lastname: Steyn
authors.forename: Cloete
authors.initials: C
authors.lastname: van Vuuren
authors.forename: Paolo
authors.initials: P
authors.lastname: Paioni
authors.forename: Pieter
authors.initials: P
authors.lastname: Jooste
authors.forename: Anthony
authors.initials: A
authors.lastname: Ogwu
authors.forename: Roger
authors.initials: R
authors.lastname: Shapiro
authors.forename: Zenele
authors.initials: Z
authors.lastname: Mncube
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
mesh_terms: D000328:Adult; D000353:Africa, Southern; D000483:Alleles; D000704:Analysis of Variance; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D005787:Gene Frequency; D005838:Genotype; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics*; D015810:Linkage Disequilibrium; D012107:Research Design; D014766:Viremia / Q000235:genetics* / Q000276:immunology / Q000821:virology
chemical_list: D006680:HLA Antigens