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

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.
Competing Interests: Declaration of interests E.J.R., B.D.W., and G.D.G. have filed patent application PCT/US2020/022403.
(Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)