Article: article from journal or magazin.
The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.
Science (new York, N.y.)
International HIV Controllers Study
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't Publication Status: ppublish
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.
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 Long-Term Survivors, HIV-1/immunology, HLA-A Antigens/chemistry, HLA-A Antigens/genetics, HLA-B Antigens/chemistry, HLA-B Antigens/genetics, HLA-C Antigens/chemistry, HLA-C Antigens/genetics, Haplotypes, Hispanic Americans/genetics, Humans, Immunity, Innate, Logistic Models, Models, Molecular, Polymorphism, Single Nucleotide, Protein Conformation, Viral Load
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