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

Henrik N Kløverpris; Mikkel Harndahl; Alasdair J Leslie; Jonathan M Carlson; Nasreen Ismail; Mary van der Stok; Kuan-Hsiang Gary Huang; Fabian Chen; Lynn Riddell; Dewald Steyn; Dominique Goedhals; Cloete van Vuuren; John Frater; Bruce D Walker; Mary Carrington; Thumbi Ndung'u; Søren Buus; Philip Goulder

doi:10.1128/JVI.01020-12

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

Henrik N Kløverpris, Mikkel Harndahl, Alasdair J Leslie, Jonathan M Carlson, Nasreen Ismail, Mary van der Stok, Kuan-Hsiang Gary Huang, Fabian Chen, Lynn Riddell, Dewald Steyn, Dominique Goedhals, Cloete van Vuuren, John Frater, Bruce D Walker, Mary Carrington, Thumbi Ndung'u, Søren Buus, Philip Goulder

LUKKET: Institut for Immunologi og Mikrobiologi

30 Citationer (Scopus)

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 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.

Originalsprog	Engelsk
Tidsskrift	Journal of Virology
Vol/bind	86
Udgave nummer	21
Sider (fra-til)	11493-11500
Antal sider	8
ISSN	0022-538X
DOI	https://doi.org/10.1128/JVI.01020-12
Status	Udgivet - nov. 2012

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10.1128/JVI.01020-12

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Kløverpris, H. N., Harndahl, M., Leslie, A. J., Carlson, J. M., Ismail, N., van der Stok, M., Huang, K-H. G., Chen, F., Riddell, L., Steyn, D., Goedhals, D., van Vuuren, C., Frater, J., Walker, B. D., Carrington, M., Ndung'u, T., Buus, S., & Goulder, P. (2012). HIV control through a single nucleotide on the HLA-B locus. Journal of Virology, 86(21), 11493-11500. https://doi.org/10.1128/JVI.01020-12

Kløverpris, HN, Harndahl, M, Leslie, AJ, Carlson, JM, Ismail, N, van der Stok, M, Huang, K-HG, Chen, F, Riddell, L, Steyn, D, Goedhals, D, van Vuuren, C, Frater, J, Walker, BD, Carrington, M, Ndung'u, T, Buus, S & Goulder, P 2012, 'HIV control through a single nucleotide on the HLA-B locus', Journal of Virology, bind 86, nr. 21, s. 11493-11500. https://doi.org/10.1128/JVI.01020-12

@article{f3daaa8ca01b4bc7babb0ef36238e070,

title = "HIV control through a single nucleotide on the HLA-B locus",

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 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.",

keywords = "Adult, Alleles, Disease Resistance, HIV Infections, HIV-1, HLA-B27 Antigen, Humans, Polymorphism, Single Nucleotide, Viral Load",

author = "Kl{\o}verpris, {Henrik N} and Mikkel Harndahl and Leslie, {Alasdair J} and Carlson, {Jonathan M} and Nasreen Ismail and {van der Stok}, Mary and Huang, {Kuan-Hsiang Gary} and Fabian Chen and Lynn Riddell and Dewald Steyn and Dominique Goedhals and {van Vuuren}, Cloete and John Frater and Walker, {Bruce D} and Mary Carrington and Thumbi Ndung'u and S{\o}ren Buus and Philip Goulder",

year = "2012",

month = nov,

doi = "10.1128/JVI.01020-12",

language = "English",

volume = "86",

pages = "11493--11500",

journal = "Journal of Virology",

issn = "0022-538X",

publisher = "American Society for Microbiology",

number = "21",

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TY - JOUR

T1 - HIV control through a single nucleotide on the HLA-B locus

AU - Kløverpris, Henrik N

AU - Harndahl, Mikkel

AU - Leslie, Alasdair J

AU - Carlson, Jonathan M

AU - Ismail, Nasreen

AU - van der Stok, Mary

AU - Huang, Kuan-Hsiang Gary

AU - Chen, Fabian

AU - Riddell, Lynn

AU - Steyn, Dewald

AU - Goedhals, Dominique

AU - van Vuuren, Cloete

AU - Frater, John

AU - Walker, Bruce D

AU - Carrington, Mary

AU - Ndung'u, Thumbi

AU - Buus, Søren

AU - Goulder, Philip

PY - 2012/11

Y1 - 2012/11

N2 - 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.

AB - 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.

KW - Adult

KW - Alleles

KW - Disease Resistance

KW - HIV Infections

KW - HIV-1

KW - HLA-B27 Antigen

KW - Humans

KW - Polymorphism, Single Nucleotide

KW - Viral Load

U2 - 10.1128/JVI.01020-12

DO - 10.1128/JVI.01020-12

M3 - Journal article

C2 - 22896606

SN - 0022-538X

VL - 86

SP - 11493

EP - 11500

JO - Journal of Virology

JF - Journal of Virology

IS - 21

ER -

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

Abstract

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