Fine-mapping classical HLA variation associated with durable host control of HIV-1 infection in African Americans

P.J. McLaren; S. Ripke; K. Pelak; A.C. Weintrob; N.A. Patsopoulos; X. Jia; R.L. Erlich; N.J. Lennon; C.M. Kadie; D. Heckerman; N. Gupta; D.W. Haas; S.G. Deeks; F. Pereyra; B.D. Walker; P.I.W. de Bakker; M. John

doi:10.1093/hmg/dds226

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Fine-mapping classical HLA variation associated with durable host control of HIV-1 infection in African Americans

Journal article

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Fine-mapping classical HLA variation associated with durable host control of HIV-1 infection in African Americans

P.J. McLaren, S. Ripke, K. Pelak, A.C. Weintrob, N.A. Patsopoulos, X. Jia, R.L. Erlich, N.J. Lennon, C.M. Kadie, D. Heckerman, …

Human Molecular Genetics, Vol.21(19), pp.4334-4347

2012

DOI: https://doi.org/10.1093/hmg/dds226

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Abstract

A small proportion of human immunodeficiency virus-1 (HIV-1) infected individuals, termed HIV-1 controllers, suppress viral replication to very low levels in the absence of therapy. Genetic investigations of this phenotype have strongly implicated variation in the class I major histocompatibility complex (MHC) region as key to HIV-1 control. We collected sequence-based classical class I HLA genotypes at 4-digit resolution in HIV-1-infected African American controllers and progressors (n = 1107), and tested them for association with host control using genome-wide single nucleotide polymorphism data to account for population structure. Several classical alleles at HLA-B were associated with host control, including B*57:03 [odds ratio (OR) = 5.1; P= 3.4 × 10(-18)] and B*81:01 (OR = 4.8; P= 1.3 × 10(-9)). Analysis of variable amino acid positions demonstrates that HLA-B position 97 is the most significant association with host control in African Americans (omnibus P = 1.2 × 10(-21)) and explains the signal of several HLA-B alleles, including B*57:03. Within HLA-B, we also identified independent effects at position 116 (omnibus P= 2.8 × 10(-15)) in the canonical F pocket, position 63 in the B pocket (P= 1.5 × 10(-3)) and the non-pocket position 245 (P= 8.8 × 10(-10)), which is thought to influence CD8-binding kinetics. Adjusting for these HLA-B effects, there is evidence for residual association in the MHC region. These results underscore the key role of HLA-B in affecting HIV-1 replication, likely through the molecular interaction between HLA-B and viral peptides presented by infected cells, and suggest that sites outside the peptide-binding pocket also influence HIV-1 control.

Details

Title: Fine-mapping classical HLA variation associated with durable host control of HIV-1 infection in African Americans
Authors/Creators: P.J. McLaren (Author/Creator)
S. Ripke (Author/Creator) - Broad Institute
K. Pelak (Author/Creator) - Duke University
A.C. Weintrob (Author/Creator) - Uniformed Services University of the Health Sciences
N.A. Patsopoulos (Author/Creator) - Brigham and Women's Hospital
X. Jia (Author/Creator) - Harvard–MIT Division of Health Sciences and Technology
R.L. Erlich (Author/Creator) - Broad Institute
N.J. Lennon (Author/Creator) - Broad Institute
C.M. Kadie (Author/Creator) - 9Microsoft Research, Redmond, WA, USA,
D. Heckerman (Author/Creator) - 10Microsoft Research, Los Angeles, CA, USA,
N. Gupta (Author/Creator) - Broad Institute
D.W. Haas (Author/Creator) - Vanderbilt University
S.G. Deeks (Author/Creator) - University of California, San Francisco
F. Pereyra (Author/Creator) - Massachusetts Institute of Technology
B.D. Walker (Author/Creator) - Howard Hughes Medical Institute
P.I.W. de Bakker (Author/Creator) - 1Division of Genetics,
M. John (Author/Creator)
Publication Details: Human Molecular Genetics, Vol.21(19), pp.4334-4347
Publisher: Oxford University Press
Identifiers: 991005543746207891
Copyright: © 2012 The Author.
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article
Additional Information: Mina John appears courtesy of the International HIV controllers study group

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.66 HIV; 1.66.46 HIV Pathogenesis
Web Of Science research areas: Biochemistry & Molecular Biology; Genetics & Heredity
ESI research areas: Molecular Biology & Genetics