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

Details

Serval ID
serval:BIB_4A4E20C0A676
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
HLA Heterozygote Advantage against HIV-1 Is Driven by Quantitative and Qualitative Differences in HLA Allele-Specific Peptide Presentation.
Journal
Molecular biology and evolution
Author(s)
Arora J., Pierini F., McLaren P.J., Carrington M., Fellay J., Lenz T.L.
ISSN
1537-1719 (Electronic)
ISSN-L
0737-4038
Publication state
Published
Issued date
01/03/2020
Peer-reviewed
Oui
Volume
37
Number
3
Pages
639-650
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.
Keywords
Antigen Presentation, Genetic Variation, Genome, Viral, HIV Infections/genetics, HIV Infections/immunology, HIV Infections/virology, HIV-1/immunology, HIV-1/physiology, HLA Antigens/genetics, HLA Antigens/immunology, HLA-B Antigens/genetics, Heterozygote, Humans, Peptides/immunology, Viral Load, Viral Proteins/chemistry, MHC evolution, antigen presentation, divergent allele advantage, human leukocyte antigen, major histocompatibility complex, pathogen-mediated balancing selection
Pubmed
Web of science
Open Access
Yes
Create date
24/11/2020 21:34
Last modification date
27/11/2020 6:26
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