Journal article
Fine-mapping classical HLA variation associated with durable host control of HIV-1 infection in African Americans
Human molecular genetics, Vol.21(19), pp.4334-4347
10/01/2012
DOI: 10.1093/hmg/dds226
PMCID: PMC3441117
PMID: 22718199
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: Subtitle
- Fine-mapping classical HLA variation associated with durable host control of HIV-1 infection in African Americans
- Creators
- Paul J McLaren - Broad Institute of Harvard and MITStephan Ripke - Broad Institute of Harvard and MITKimberly Pelak - Center for Human Genome Variation, Duke University School of MedicineAmy C Weintrob - Uniformed Services University of the Health SciencesNikolaos A Patsopoulos - Department of Neurology, Brigham and Women's Hospital, Harvard Medical SchoolXiaoming Jia - Harvard-MIT Division of Health Sciences and TechnologyRachel L Erlich - Broad Institute of Harvard and MITNiall J Lennon - Broad Institute of Harvard and MITCarl M Kadie - Microsoft ResearchDavid Heckerman - Microsoft ResearchNamrata Gupta - Broad Institute of Harvard and MITDavid W Haas - Vanderbilt University School of MedicineSteven G Deeks - University of CaliforniaFlorencia Pereyra - Massachusetts Institute of Technology and HarvardBruce D Walker - Massachusetts Institute of Technology and HarvardPaul I. W de Bakker - Department of Neurology, Brigham and Women's Hospital, Harvard Medical SchoolInternational HIV Controllers Study
- Contributors
- Jack T Stapleton (Contributor) - University of Iowa, Internal Medicine
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.21(19), pp.4334-4347
- Publisher
- Oxford University Press
- DOI
- 10.1093/hmg/dds226
- PMID
- 22718199
- PMCID
- PMC3441117
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Language
- English
- Date published
- 10/01/2012
- Academic Unit
- Microbiology and Immunology; Infectious Diseases; Internal Medicine
- Record Identifier
- 9984094493202771
Metrics
17 Record Views