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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.