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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 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.

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