The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.
Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology (MIT) and Harvard, Boston, MA, USA.
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Pereyra
Xiaoming
X
Jia
Paul J
PJ
McLaren
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Paul I W
PI
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Bruce D
BD
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Stephan
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Ripke
Chanson J
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Sara L
SL
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Carrington
Carl M
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Kadie
Jonathan M
JM
Carlson
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Heckerman
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Davies
Amy
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Jamie M
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Moore
Nicole
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Beattie
Supriya
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Gupta
Andrew
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Namrata
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Gao
Ying
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Yuko
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Piechocka-Trocha
Emily
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Cutrell
Rachel
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Rosenberg
Kristin L
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Paul
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O'Leary
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Schaefer
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D001741:Black or African American / Q000235:genetics; D000483:Alleles; D000596:Amino Acids / Q000502:physiology; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015331:Cohort Studies; D018450:Disease Progression; D005805:Genes, MHC Class I; D055106:Genome-Wide Association Study; D015488:HIV Antigens / Q000276:immunology; D015658:HIV Infections / Q000208:ethnology / Q000235:genetics* / Q000276:immunology* / Q000821:virology; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000276:immunology; D015234:HLA-A Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015235:HLA-B Antigens / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015236:HLA-C Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006239:Haplotypes; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate; D016015:Logistic Models; D008958:Models, Molecular; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D019562:Viral Load; D044465:White People / Q000235:genetics
D000596:Amino Acids; D015488:HIV Antigens; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens