The HLA class-II immunopeptidomes of AAV capsids proteins

Frontiers in Immunology

Immunology

Carlos A. Brito-Sierra¹  Megan B. Lannan¹  Robert W. Siegel¹  Laurent P. Malherbe¹ 

[1] Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States;

关键词: AAV (Adeno-associated virus);    immunogenicity;    immunopeptidome;    gene therapy;    risk assessment;    CD4+;    HLA;   

DOI  :  10.3389/fimmu.2022.1067399

 received in 2022-10-11, accepted in 2022-11-30,  发布年份 2022

来源: Frontiers

【 摘 要 】

IntroductionGene therapies are using Adeno-associated viruses (AAVs) as vectors, but immune responses against the capsids pose challenges to their efficiency and safety. Helper T cell recognition of capsid-derived peptides bound to human leukocyte antigen (HLA) class II molecules is an essential step in the AAV-specific adaptive immunity.MethodsUsing MHC-associated peptide proteomics, we identified the HLA-DR and HLA-DQ immunopeptidomes of the capsid proteins of three different AAV serotypes (AAV2, AAV6, and AAV9) from a panel of healthy donors selected to represent a majority of allele usage.ResultsThe identified sequences span the capsids of all serotypes, with AAV2 having the highest peptide count. For all the serotypes, multiple promiscuous peptides were identified and displayed by both HLA-DR and -DQ. However, despite high sequence homology, there were few identical peptides among AAV2, AAV6, and AAV9 immunopeptidomes, and none were promiscuous.DiscussionResults from this work represent a comprehensive immunopeptidomics research of potential CD4+ T cell epitopes and provide the basis for immunosurveillance efforts for safer and more efficient AAV-based gene therapies.

【 授权许可】

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Copyright © 2022 Brito-Sierra, Lannan, Siegel and Malherbe