HIV control through a single nucleotide on the HLA-B locus.

TitleHIV control through a single nucleotide on the HLA-B locus.
Publication TypeJournal Article
Year of Publication2012
AuthorsKløverpris 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
JournalJ Virol
Date Published2012 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 JournalJ. Virol.
PubMed ID22896606