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- Title
Variable HIV peptide stability in human cytosol is critical to epitope presentation and immune escape.
- Authors
Lazaro, Estibaliz; Kadie, Carl; Stamegna, Pamela; Shao Chong Zhang; Gourdain, Pauline; Lai, Nicole Y.; Mei Zhang; Martinez, Sergio A.; Heckerman, David; Le Gall, Sylvie; Zhang, Shao Chong; Zhang, Mei
- Abstract
Induction of virus-specific CD8⁺ T cell responses is critical for the success of vaccines against chronic viral infections. Despite the large number of potential MHC-I-restricted epitopes located in viral proteins, MHC-I-restricted epitope generation is inefficient, and factors defining the production and presentation of MHC-I-restricted viral epitopes are poorly understood. Here, we have demonstrated that the half-lives of HIV-derived peptides in cytosol from primary human cells were highly variable and sequence dependent, and significantly affected the efficiency of cell recognition by CD8⁺ T cells. Furthermore, multiple clinical isolates of HLA-associated HIV epitope variants displayed reduced half-lives relative to consensus sequence. This decreased cytosolic peptide stability diminished epitope presentation and CTL recognition, illustrating a mechanism of immune escape. Chaperone complexes including Hsp90 and histone deacetylase HDAC6 enhanced peptide stability by transient protection from peptidase degradation. Based on empirical results with 166 peptides, we developed a computational approach utilizing a sequence-based algorithm to estimate the cytosolic stability of antigenic peptides. Our results identify sequence motifs able to alter the amount of peptide available for loading onto MHC-I, suggesting potential new strategies to modulate epitope production from vaccine immunogens.
- Subjects
PEPTIDES; CYTOSOL; EPITOPES; MOLECULAR chaperones; HISTONE deacetylase; VIRUS diseases; LABORATORY mice; AIDS vaccines; ALGORITHMS; AMINO acids; ANTIGENS; BIOCHEMISTRY; CELLULAR immunity; COMPARATIVE studies; DOCUMENTATION; HIV; HYDROLASES; IMMUNITY; PHENOMENOLOGY; RESEARCH methodology; MEDICAL cooperation; MOLECULAR structure; PROTEINS; RESEARCH; RESEARCH funding; T cells; TIME; VIRAL antigens; HLA-B27 antigen; BIOINFORMATICS; EVALUATION research; IN vitro studies
- Publication
Journal of Clinical Investigation, 2011, Vol 121, Issue 6, p2480
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI44932