HLA Heterozygote Advantage against HIV-1 Is Driven by Quantitative and Qualitative Differences in HLA Allele-Specific Peptide Presentation

Arora, JatinPierini, FedericaMcLaren, Paul J.Carrington, MaryFellay, JacquesLenz, Tobias L.2020-04-172020-04-172020-04-172020-03-0110.1093/molbev/msz249https://infoscience.epfl.ch/handle/20.500.14299/168231WOS:000522244100003Pathogen-mediated balancing selection is regarded as a key driver of host immunogenetic diversity. A hallmark for balancing selection in humans is the heterozygote advantage at genes of the human leukocyte antigen (HLA), resulting in improved HIV-1 control. However, the actual mechanism of the observed heterozygote advantage is still elusive. HLA heterozygotes may present a broader array of antigenic viral peptides to immune cells, possibly resulting in a more efficient cytotoxic T-cell response. Alternatively, heterozygosity may simply increase the chance to carry the most protective HLA alleles, as individual HLA alleles are known to differ substantially in their association with HIV-1 control. Here, we used data from 6,311 HIV-1-infected individuals to explore the relative contribution of quantitative and qualitative aspects of peptide presentation in HLA heterozygote advantage against HIV. Screening the entire HIV-1 proteome, we observed that heterozygous individuals exhibited a broader array of HIV-1 peptides presented by their HLA class I alleles. In addition, viral load was negatively correlated with the breadth of the HIV-1 peptide repertoire bound by an individuals HLA variants, particularly at HLA-B. This suggests that heterozygote advantage at HLA-B is at least in part mediated by quantitative peptide presentation. We also observed higher HIV-1 sequence diversity among HLA-B heterozygous individuals, suggesting stronger evolutionary pressure from HLA heterozygosity. However, HLA heterozygotes were also more likely to carry certain HLA alleles, including the highly protective HLA-B*57:01 variant, indicating that HLA heterozygote advantage ultimately results from a combination of quantitative and qualitative effects in antigen presentation.Biochemistry & Molecular BiologyEvolutionary BiologyGenetics & Hereditymajor histocompatibility complexmhc evolutionpathogen-mediated balancing selectiondivergent allele advantagehuman leukocyte antigenantigen presentationmultiple sequence alignmentmhc class-ilinkage disequilibriumbalancing selectionnatural-selectionevolutiondiversitydivergentHLA Heterozygote Advantage against HIV-1 Is Driven by Quantitative and Qualitative Differences in HLA Allele-Specific Peptide Presentationtext::journal::journal article::research article