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HIV peptidome-wide association study reveals patient-specific epitope repertoires associated with HIV control.

  • Arora J Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, 24306 Plön, Germany.
  • McLaren PJ JC Wilt Infectious Diseases Research Center, Public Health Agency of Canada, Winnipeg, R3E 0W3, Canada.
  • Chaturvedi N Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
  • Carrington M Cancer and Inflammation Program, Leidos Biomedical Research, Frederick National Laboratory, Frederick, MD 21702.
  • Fellay J Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
  • Lenz TL Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, 24306 Plön, Germany; lenz@post.harvard.edu.
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  • 2019-01-04
Published in:
  • Proceedings of the National Academy of Sciences of the United States of America. - 2019
HIV-1
HLA
MHC
antigen presentation
epitope prediction
Acquired Immunodeficiency Syndrome
Antigens, Viral
Epitopes
Genetic Variation
Genome-Wide Association Study
HIV-1
HLA Antigens
Humans
Proteome
English Genetic variation in the peptide-binding groove of the highly polymorphic HLA class I molecules has repeatedly been associated with HIV-1 control and progression to AIDS, accounting for up to 12% of the variation in HIV-1 set point viral load (spVL). This suggests a key role in disease control for HLA presentation of HIV-1 epitopes to cytotoxic T cells. However, a comprehensive understanding of the relevant HLA-bound HIV epitopes is still elusive. Here we describe a peptidome-wide association study (PepWAS) approach that integrates HLA genotypes and spVL data from 6,311 HIV-infected patients to interrogate the entire HIV-1 proteome (3,252 unique peptides) for disease-relevant peptides. This PepWAS approach predicts a core set of epitopes associated with spVL, including known epitopes but also several previously uncharacterized disease-relevant peptides. More important, each patient presents only a small subset of these predicted core epitopes through their individual HLA-A and HLA-B variants. Eventually, the individual differences in these patient-specific epitope repertoires account for the variation in spVL that was previously associated with HLA genetic variation. PepWAS thus enables a comprehensive functional interpretation of the robust but little-understood association between HLA and HIV-1 control, prioritizing a short list of disease-associated epitopes for the development of targeted therapy.
Language
  • English
Open access status
bronze
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https://sonar.ch/global/documents/177485
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