HIV control through a single nucleotide on the HLA-B locus.
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 log(10) lower 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.
Department of Paediatrics, University of Oxford, Oxford, United Kingdom. henrik.kloverpris@paediatrics.ox.ac.uk
Henrik N
HN
Kløverpris
Mikkel
M
Harndahl
Alasdair J
AJ
Leslie
Jonathan M
JM
Carlson
Nasreen
N
Ismail
Mary
M
van der Stok
Kuan-Hsiang Gary
KH
Huang
Fabian
F
Chen
Lynn
L
Riddell
Dewald
D
Steyn
Dominique
D
Goedhals
Cloete
C
van Vuuren
John
J
Frater
Bruce D
BD
Walker
Mary
M
Carrington
Thumbi
T
Ndung'u
Søren
S
Buus
Philip
P
Goulder
D000328:Adult; D000483:Alleles; D060467:Disease Resistance; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000302:isolation & purification; D015796:HLA-B27 Antigen / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D019562:Viral Load
C090660:HLA-B protein, human; D015796:HLA-B27 Antigen