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

  1. Author:
    Arora, Jatin
    Pierini, Federica
    McLaren, Paul J
    Carrington,Mary
    Fellay, Jacques
    Lenz, Tobias L

  2. Author Address

    Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Pl 246;n, Germany., JC Wilt Infectious Diseases Research Center, National HIV and Retrovirology Laboratory, Public Health Agency of Canada, R3E 0W3, Winnipeg, Canada., Department of Medical Microbiology and Infectious Diseases, University of Manitoba, R3E 0J9, Winnipeg Canada., Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA., Global Health Institute, School of Life Sciences, 201;cole Polytechnique F 233;d 233;rale de Lausanne, Lausanne, Switzerland., Swiss Institute of Bioinformatics, Lausanne, Switzerland., Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.,
    1. Year: 2020
    2. Date: MAR
    3. Epub Date: 2019 10 25
  2. Journal: Molecular biology and evolution
    1. 37
    2. 3
    3. Pages: 639-650
  4. Type of Article: Article
  5. ISSN: 0737-4038
  1. 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. © The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

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External Sources

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  2. DOI: 10.1093/molbev/msz249
  3. PMID: 31651980
  4. View record in Web of Science®
  5. WOS: 000522244100003
  6. PII : 5607306

Library Notes

  1. Fiscal Year: FY2019-2020
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