Fine-mapping classical HLA variation associated with durable host control of HIV-1 infection in African Americans.
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.
Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
Paul J
PJ
McLaren
Stephan
S
Ripke
Kimberly
K
Pelak
Amy C
AC
Weintrob
Nikolaos A
NA
Patsopoulos
Xiaoming
X
Jia
Rachel L
RL
Erlich
Niall J
NJ
Lennon
Carl M
CM
Kadie
David
D
Heckerman
Namrata
N
Gupta
David W
DW
Haas
Steven G
SG
Deeks
Florencia
F
Pereyra
Bruce D
BD
Walker
Paul I W
PI
de Bakker
D001741:Black or African American / Q000235:genetics*; D060467:Disease Resistance; D014644:Genetic Variation; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D020641:Polymorphism, Single Nucleotide
D006680:HLA Antigens; D015235:HLA-B Antigens