Immunogenetics of spontaneous control of HIV

Abstract

Host genetic variation is presently estimated to account for about one-fourth of the observed differences in control of HIV across infected individuals. Genome-wide association studies have confirmed that polymorphism within the HLA class I locus is the primary host genetic contributor to determining outcome after infection. Here we progress beyond the genetic associations alone to consider the functional explanations for these correlations. In this process, the complex and multidimensional effects of HLA molecules in viral disease become apparent.

Figure 1

GWAS analysis: individual “tagging SNPs” are measured by chip technology. Owing to linkage disequilibrium, the tagging SNP provides reliable information about surrounding SNPs, allowing the majority of variability in the human genome to be determined by measuring only one million of its three billion nucleotides. Abbreviations: GWAS, genome-wide association study; SNP, single-nucleotide polymorphism.

Figure 2

Manhattan plot of data derived from 974 HIV controllers and 2,648 progressors. Shown are p-values for 1,384,048 data points derived from comparing each measured single-nucleotide polymorphism (SNP) in HIV controllers versus progressors. 313 SNPs reach statistical significance in this population of European ancestry, appearing as a line, which is defined by p < 5 × 10⁻⁸ because of the need to correct for multiple comparisons. All significant SNPs lie within the major histocompatibility complex on chromosome 6.

Figure 3

Three-dimensional ribbon representation of the HLA-B protein showing amino acid positions 62, 63, 67, 70, and 97 lining the peptide-binding groove. The peptide backbone of the epitope is also displayed. Adapted from Reference with permission.

Figure 4

Alignment of full-length 3′ untranslated region (UTR) sequences of the common HLA-C alleles. Identical nucleotides are shown as dots, and deletions are indicated by hyphens. The miR-148 binding site is located within the blue boxed segment, where those alleles with an insertion at position 263 bind miR-148a and are downregulated, but those with a deletion at this position escape microRNA binding and downregulation.