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

Arora, J., McLaren, P. J., Chaturvedi, N., Carrington, M., Fellay, J., & Lenz, T. L. (2019). HIV peptidome-wide association study reveals patient-specific epitope repertoires associated with HIV control. Proc Natl Acad Sci USA, 116(3). Retrieved from http://www.pnas.org/content/116/3/944.abstract.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-C896-3 Version Permalink: http://hdl.handle.net/21.11116/0000-0002-C8BA-B
Genre: Journal Article

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 Creators:
Arora, Jatin1, 2, Author              
McLaren, Paul J., Author
Chaturvedi, Nimisha, Author
Carrington, Mary, Author
Fellay, Jacques, Author
Lenz, Tobias L.1, Author              
Affiliations:
1Emmy Noether Research Group Evolutionary Immunogenomics, Department Evolutionary Ecology, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_2068286              
2IMPRS for Evolutionary Biology, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_1445639              

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Free keywords: HLA; MHC; HIV-1; epitope prediction; antigen presentation
 Abstract: Individual differences in HIV-1 control and progression to AIDS have been pinpointed to genetic variation in the HLA, coding for antigen-presenting molecules. However, our understanding of the corresponding antigens is still incomplete. Here we developed an approach that combines HLA genotypes and viral load data of HIV-infected individuals to screen the entire HIV-1 proteome for disease-relevant peptides. Our PepWAS approach identified a limited manageable core set of peptides, accounting for the entire variation in viral load previously associated with genetic variation in the HLA. This core set of disease-relevant antigens thus provides a functional link between HLA genetic variation and HIV-1 control, confirming several known antigens, but also prioritizing previously undescribed antigens as potential therapeutic targets.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.

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Language(s): eng - English
 Dates: 2018-07-202018-12-062019-01-022019-01-15
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
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Title: Proc Natl Acad Sci USA
Source Genre: Journal
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Publ. Info: -
Pages: 944 Volume / Issue: 116 (3) Sequence Number: - Start / End Page: - Identifier: -

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Title: Proceedings of the National Academy of Sciences of the United States of America
  Other : Proc. Acad. Sci. USA
  Other : Proc. Acad. Sci. U.S.A.
  Other : Proceedings of the National Academy of Sciences of the USA
  Abbreviation : PNAS
Source Genre: Journal
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Publ. Info: Washington, D.C. : National Academy of Sciences
Pages: - Volume / Issue: 116 (3) Sequence Number: - Start / End Page: 944 - 949 Identifier: ISSN: 0027-8424
CoNE: https://pure.mpg.de/cone/journals/resource/954925427230