Volume 9 Supplement 2
HIV control through a single nucleotide on the HLA-I locus
© Kløverpris et al; licensee BioMed Central Ltd. 2012
Published: 13 September 2012
In correlative studies HLA class I type is consistently found to have the strongest impact on HIV disease progression. However, the exact mechanism involved is complicated by several factors; many alleles are ligands for NK cells as well as CD8 T-cells, and strong linkage disequilibrium between Class I alleles makes it difficult to distinguish the effect of individual alleles from other HLAs or from other important loci found on the HLA haplotype, such as the recently described -35 SNP.
Here we study two recently diverged HLA alleles, B*4201 and B*4202, which only differ by a single amino acid. Crucially, they occur primarily on identical Class I haplotypes and do not act as NK cell ligands. Therefore, they represent a unique opportunity to study the impact of a single HLA allele on HIV immune control not confounded by other genetic factors in a large outbred cohort (n=2,093) of C-clade infected individuals.
Here we show that the amino acid change in position 9 of the HLA-B molecule, is critical for peptide binding and significantly alters the Gag CTL epitopes targeted (P=2x10-10), measured both directly ex-vivo by ELISPOT and indirectly through CTL escape mutation (P=2x10-8). Strikingly, HLA-B*4201 is associated with significantly lower viral load setpoint than HLA-B*4202 (P=0.02).
This naturally controlled experiment represents perhaps the clearest demonstration of the direct impact of particular HIV Gag specific CTL on disease control.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.