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Science 330 (6010): 1551-1557

Copyright © 2010 by the American Association for the Advancement of Science

The Major Genetic Determinants of HIV-1 Control Affect HLA Class I Peptide Presentation

The International HIV Controllers Study*,{dagger}

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.

* All authors with their contributions and affiliations appear at the end of this paper.

{dagger} To whom correspondence should be addressed. E-mail: bwalker{at}partners.org (B.D.W.); pdebakker{at}rics.bwh.harvard.edu (P.I.W.d.B.)

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