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

Getting HIV Under Control Approximately 1 in 300 people infected with HIV are HIV “controllers” who are able to maintain long-term control of the virus without medication and who do not progress to AIDS. Uncovering the genetic basis for this ability is of great interest. Pereyra et al. (p. 1551, published online 4 November; see the Perspective by McMichael and Jones) now present genome-wide association results from patients enrolled in the International HIV Controllers Study. The analysis compared HIV controllers of European, African-American, and Hispanic descent with HIV progressors and found >300 variants that reached genome-wide significance, all of which were in the major histocompatibility class I (HLA) region on chromosome 6. Analysis of the effects of individual amino acids within classical HLA proteins revealed six independently significant residues, five of which lined the peptide-binding groove. Thus, differences in binding to viral peptide antigens by HLA may be the major factors underlying genetic differences between HIV controllers and progressors. MHC class I alleles are the major genetic determinants associated with people able to control HIV infection without therapy. 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.