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

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.

Fig. 1

Genome-wide association results in the European sample. (A) Manhattan plot of 1.3 million autosomal SNPs. Only SNPs in the MHC on chromosome 6 reach genome-wide significance, indicated by the horizontal dotted line (P < 5 × 10⁻⁸). Red and blue colors alternate between chromosomes. (B) Quantile-quantile plot of the association results with (black) and without (blue) SNPs in the extended MHC and the CCR5-CCR2 locus, indicating that the detectable effect is entirely attributable to these two loci. The red line denotes the expected distribution under the null hypothesis of no effect. (C) Distribution of the genotype protective score, defined as the total number of alleles associated with host control at the four independent SNPs in the MHC and the variants at CCR5-CCR2, showing marked differences in controllers (orange) and progressors (blue). In aggregate, these variants explain 23% of the observed variance of durable host control.

Fig. 2

Imputation quality of classical HLA alleles in the European sample. (A) Concordance between imputed (y-axis) and observed (x-axis) frequencies of classical HLA types in 371 HIV-1 controllers with four-digit HLA types obtained through Sanger sequencing. (B) Positive predictive value, sensitivity, and genotype correlation (r²) with typed alleles as a function of the observed frequency.

Fig. 3

Associations at amino acids in HLA-B in the European sample. (A) Association results for all variable amino acid positions, as calculated by the omnibus test. Colors denote conventional pocket positions. P values for significant classical HLA-B alleles are shown for comparison. (B) Marked allele frequency differences between controllers and progressors for amino acids at positions 67, 70, and 97. Numbers above the bars indicate odds ratios (values >1 indicate a protective effect). (C) Associations between allelic variants at amino acid positions 67, 70, and 97 and quantitative virus load set point in the independent Swiss HIV cohort study. Effect estimates (beta coefficients from a linear-regression model) are given in log₁₀ units of virus load set point. P values refer to the omnibus test for association at each position. Error bars indicate the standard error of the beta coefficient.

Fig. 4

Three-dimensional ribbon representation of the HLA-B protein based on Protein Data Bank entry 2bvp (30), highlighting amino acid positions 62, 63, 67, 70, and 97 lining the peptide binding pocket. The peptide backbone of the epitope is also displayed. This figure was prepared with UCSF Chimera (32).