Journal
HUMAN MOLECULAR GENETICS
Volume 21, Issue 19, Pages 4334-4347Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/dds226
Keywords
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Funding
- Collaboration for AIDS Vaccine Discovery (CAVD) of the Bill and Melinda Gates Foundation
- Harvard University Center for AIDS Research [P-30-AI060354]
- UCSF CFAR [P-30 AI27763]
- UCSF CTSI [UL1 RR024131]
- CNICS [R24 AI067039]
- Vanderbilt CTSA [RR024975]
- NIH [AI28568, AI030914, AI087145, K24AI069994, AI069513, AI34835, AI069432, AI069423, AI069477, AI069501, AI069474, AI069428, AI69467]
- Infectious Disease Clinical Research Program (IDCRP)
- Department of Defense (DoD) through the Uniformed Services University of the Health Sciences
- National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), under Inter-Agency Agreement [Y1-AI-5072]
- The NIH [RR024975, AI069415, Al32782, AI27661, AI25859, AI30914, AI069495, AI069471, AI069532, AI069452, AI069450, AI069556, AI069484, AI069472, AI34853, AI069465, AI069511, AI38844, AI069424, AI069434, AI46370, AI68634, AI069502, AI069419, AI068636, AI077505, MH071205]
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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 B57:03 [odds ratio (OR) 5.1; P 3.4 10(18)] and B81:01 (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 B57:03. 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.
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