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<jats:p>Peptides generated by proteasome-catalyzed splicing of noncontiguous amino acid sequences have been shown to constitute a source of nontemplated human leukocyte antigen class I (HLA-I) epitopes, but their role in pathogen-specific immunity remains unknown. CD8<jats:sup>+</jats:sup> T cells are key mediators of HIV type 1 (HIV-1) control, and identification of novel epitopes to enhance targeting of infected cells is a priority for prophylactic and therapeutic strategies. To explore the contribution of proteasome-catalyzed peptide splicing (PCPS) to HIV-1 epitope generation, we developed a broadly applicable mass spectrometry-based discovery workflow that we employed to identify spliced HLA-I–bound peptides on HIV-infected cells. We demonstrate that HIV-1–derived spliced peptides comprise a relatively minor component of the HLA-I–bound viral immunopeptidome. Although spliced HIV-1 peptides may elicit CD8<jats:sup>+</jats:sup> T cell responses relatively infrequently during infection, CD8<jats:sup>+</jats:sup> T cells primed by partially overlapping contiguous epitopes in HIV-infected individuals were able to cross-recognize spliced viral peptides, suggesting a potential role for PCPS in restricting HIV-1 escape pathways. Vaccine-mediated priming of responses to spliced HIV-1 epitopes could thus provide a novel means of exploiting epitope targets typically underutilized during natural infection.</jats:p>

Original publication

DOI

10.1073/pnas.1911622116

Type

Journal article

Journal

Proceedings of the National Academy of Sciences

Publisher

Proceedings of the National Academy of Sciences

Publication Date

03/12/2019

Volume

116

Pages

24748 - 24759