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bioRxiv · 10.1101/307314

HIV Peptidome-Wide Association Study Reveals Patient-Specific Epitope Repertoires Associated with HIV Control

Arora, J.·McLaren, P.·Chaturvedi, N.·Carrington, M.·Fellay, J.·Lenz, T. L.
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Abstract

Genetic variation in the peptide-binding groove of the highly polymorphic human leukocyte antigen (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 developed 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 revealed a core set of epitopes associated with spVL, including previously characterized epitopes but also several novel disease-relevant peptides. More importantly, each patient presents only 16 ({+/-}7) and 6 ({+/-}6) of these core epitopes through their individual HLA-B and HLA-A variants, respectively. Differences in these patient-specific epitope repertoires account for almost all the variation in spVL 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 and targetable list of disease-associated epitopes for personalized immunotherapy.

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Arora, J., McLaren, P., Chaturvedi, N., Carrington, M., Fellay, J., Lenz, T. L.. 2018-04-24. HIV Peptidome-Wide Association Study Reveals Patient-Specific Epitope Repertoires Associated with HIV Control. https://doi.org/10.1101/307314

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