The major genetic determinants of HIV-1 control affect HLA class I peptide presentation

Science. 2010 Dec 10;330(6010):1551-7. doi: 10.1126/science.1195271. Epub 2010 Nov 4.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • African Americans / genetics
  • Alleles
  • Amino Acids / physiology
  • Antigen Presentation*
  • CD8-Positive T-Lymphocytes / immunology
  • Cohort Studies
  • Disease Progression
  • European Continental Ancestry Group / genetics
  • Genes, MHC Class I*
  • Genome-Wide Association Study
  • HIV Antigens / immunology
  • HIV Infections / ethnology
  • HIV Infections / genetics*
  • HIV Infections / immunology*
  • HIV Infections / virology
  • HIV Long-Term Survivors
  • HIV-1* / immunology
  • HLA-A Antigens / chemistry
  • HLA-A Antigens / genetics
  • HLA-A Antigens / immunology
  • HLA-A Antigens / metabolism
  • HLA-B Antigens / chemistry
  • HLA-B Antigens / genetics*
  • HLA-B Antigens / immunology
  • HLA-B Antigens / metabolism
  • HLA-C Antigens / chemistry
  • HLA-C Antigens / genetics
  • HLA-C Antigens / immunology
  • HLA-C Antigens / metabolism
  • Haplotypes
  • Hispanic Americans / genetics
  • Humans
  • Immunity, Innate
  • Logistic Models
  • Models, Molecular
  • Polymorphism, Single Nucleotide
  • Protein Conformation
  • Viral Load

Substances

  • Amino Acids
  • HIV Antigens
  • HLA-A Antigens
  • HLA-B Antigens
  • HLA-C Antigens

Grant support