@article{kloverpris2012hiv,
author = {Kloverpris, Henrik N. and Harndahl, Mikkel and Leslie, Alasdair J. and Carlson, Jonathan M. and Ismail, Nasreen and Stok, Mary van der and Huang, Kuan-Hsiang Gary and Chen, Fabian and Riddell, Lynn and Steyn, Dewald and Goedhals, Dominique and Vuuren, Cloete van and Frater, John and Walker, Bruce D. and Carrington, Mary and Ndung'u, Thumbi and Buus, Soren and Goulder, Philip},
title = {HIV Control through a Single Nucleotide on the HLA-B Locus},
year = {2012},
month = {August},
abstract = {Genetic variation within the HLA-B locus has the strongest impact on HIV disease progression of any polymorphisms within the human genome. However, identifying 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 the 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 differ by only 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 cytotoxic T lymphocyte (CTL) epitopes targeted, measured directly ex vivo by gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay (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 log10lower viral-load set point than HLA-B*42:02 (P = 0.02), which presents no p24 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 a particular HIV-specific CTL on disease control.},
url = {http://approjects.co.za/?big=en-us/research/publication/hiv-control-single-nucleotide-hla-b-locus/},
journal = {Journal of Virology},
edition = {Journal of Virology},
}