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\u2013restricted epitopes located in viral proteins, MHC-I\u2013restricted epitope generation is inefficient, and factors defining the production and presentation of MHC-I\u2013restricted 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.<\/p>\n","protected":false},"excerpt":{"rendered":"
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\u2013restricted epitopes located in viral proteins, MHC-I\u2013restricted epitope generation is inefficient, and factors defining the production and presentation of MHC-I\u2013restricted viral epitopes are poorly understood. 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