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HLA class-I-peptide stability mediates CD8⁺ T cell immunodominance hierarchies and facilitates HLA-associated immune control of HIV.

ABSTRACT: Defining factors that govern CD8⁺ T cell immunodominance is critical for the rational design of vaccines for viral pathogens. Here, we assess the contribution of human leukocyte antigen (HLA) class-I-peptide stability for 186 optimal HIV epitopes across 18 HLA alleles using transporter associated with antigen processing (TAP)-deficient mono-allelic HLA-expressing cell lines. We find that immunodominant HIV epitopes increase surface stabilization of HLA class-I molecules in comparison to subdominant epitopes. HLA class-I-peptide stability is also strongly correlated with overall immunodominance hierarchies, particularly for epitopes from high-abundance proteins (e.g., Gag). Moreover, HLA alleles associated with HIV protection are preferentially stabilized by epitopes derived from topologically important viral regions at a greater frequency than neutral and risk alleles. These findings indicate that relative stabilization of HLA class-I is a key factor for CD8⁺ T cell epitope immunodominance hierarchies, with implications for HIV control and the design of T-cell-based vaccines.

SUBMITTER: Kaseke C

PROVIDER: S-EPMC8293625 | biostudies-literature |

REPOSITORIES: biostudies-literature

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