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  HLA heterozygote advantage against HIV-1 is driven by quantitative and qualitative differences in HLA allele-specific peptide presentation

Arora, J., Pierini, F., McLaren, P. J., Carrington, M., Fellay, J., & Lenz, T. L. (2020). HLA heterozygote advantage against HIV-1 is driven by quantitative and qualitative differences in HLA allele-specific peptide presentation. Molecular Biology and Evolution, 37(3), 639-650. doi:10.1093/molbev/msz249.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-1C43-1 Version Permalink: http://hdl.handle.net/21.11116/0000-0005-FFFB-2
Genre: Journal Article

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Arora, Jatin1, 2, Author              
Pierini, Federica1, 2, Author              
McLaren, Paul J, Author
Carrington, Mary, Author
Fellay, Jacques, Author
Lenz, Tobias L.2, Author              
Affiliations:
1IMPRS for Evolutionary Biology, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_1445639              
2Emmy Noether Research Group Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_2616693              

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 Abstract: Pathogen-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 individual’s 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.

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Language(s): eng - English
 Dates: 2019-10-252020-03
 Publication Status: Published in print
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 Identifiers: DOI: 10.1093/molbev/msz249
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Title: Molecular Biology and Evolution
  Other : Mol. Biol. Evol.
Source Genre: Journal
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Publ. Info: Oxford : Oxford University Press
Pages: - Volume / Issue: 37 (3) Sequence Number: - Start / End Page: 639 - 650 Identifier: ISSN: 0737-4038
CoNE: https://pure.mpg.de/cone/journals/resource/954925536119