Variable HIV peptide stability in human cytosol is critical to epitope presentation and immune escape |
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Authors: | Lazaro Estibaliz Kadie Carl Stamegna Pamela Zhang Shao Chong Gourdain Pauline Lai Nicole Y Zhang Mei Martinez Sergio A Heckerman David Le Gall Sylvie |
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Institution: | 1Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. 2eScience Research Group, Microsoft Research, Redmond, Washington, USA. 3eScience Research Group, Microsoft Research, Los Angeles, California, USA. |
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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. |
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