|Title||HIV control through a single nucleotide on the HLA-B locus.|
|Publication Type||Journal Article|
|Year of Publication||2012|
|Authors||Kløverpris HN, Harndahl M, Leslie AJ, Carlson JM, Ismail N, van der Stok M, Huang K-H G, Chen F, Riddell L, Steyn D, Goedhals D, van Vuuren C, Frater J, Walker BD, Carrington M, Ndung'u T, Buus S, Goulder PJR|
|Date Published||2012 Aug 15|
Genetic variation within the HLA-B locus has the strongest impact on HIV disease progression of any polymorphisms within the human genome. However, the exact mechanism involved is complicated by several factors. HLA-Bw4 alleles provide ligands for NK cells and for CD8 T-cells, and strong linkage disequilibrium between HLA class I alleles complicates discrimination of individual HLA allelic effects from those of other HLA and non-HLA alleles on the same haplotype. Here we exploit an experiment of nature, involving two recently diverged HLA alleles, HLA-B*42:01 and HLA-B*42:02, which only differ by a single amino acid. Crucially, they occur primarily on identical HLA class I haplotypes and, as Bw6 alleles, do not act as NK cell ligands, and are therefore largely unconfounded by other genetic factors. We show that in an outbred cohort (n=2,093) of HIV C-clade infected individuals, a single amino acid change at position 9 of the HLA-B molecule critically affects peptide binding and significantly alters the CTL epitopes targeted, measured directly ex-vivo by IFNγ ELISPOT (P=2×10(-10)) and functionally through CTL escape mutation (P=2×10(-8)). HLA-B*42:01, which presents multiple Gag epitopes, is associated with a 0.52 log(10) lower viral load setpoint than HLA-B*42:02 (P=0.02), which presents no Gag epitopes. The magnitude of this effect from a single amino acid difference in the HLA-A*30:01/B*42/Cw*17:01 haplotype is equivalent to 75% of that of HLA-B*57:03, the most protective HLA class I allele in this population. This naturally controlled experiment represents perhaps the clearest demonstration of the direct impact of particular HIV-specific CTL on disease control.
|Alternate Journal||J. Virol.|