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.
Publication types
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Comparative Study
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Research Support, American Recovery and Reinvestment Act
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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AIDS Vaccines
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Algorithms
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Amino Acid Motifs
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Amino Acid Sequence
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Antigen Presentation*
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Computational Biology
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Consensus Sequence
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Cytosol / immunology
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Epitopes / immunology*
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HIV Antigens / chemistry
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HIV Antigens / immunology*
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HIV Core Protein p24 / chemistry
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HIV Core Protein p24 / immunology*
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HIV Reverse Transcriptase / chemistry
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HIV Reverse Transcriptase / immunology*
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HIV-1 / immunology*
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HLA-A Antigens / immunology
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HLA-A3 Antigen
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HLA-B Antigens / immunology
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HSP90 Heat-Shock Proteins / physiology
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Half-Life
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Histone Deacetylase 6
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Histone Deacetylases / physiology
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Humans
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In Vitro Techniques
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Molecular Sequence Data
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Peptide Fragments / immunology
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Peptide Fragments / metabolism
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Protein Stability
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T-Cell Antigen Receptor Specificity*
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T-Lymphocytes, Cytotoxic / immunology*
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gag Gene Products, Human Immunodeficiency Virus / chemistry
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gag Gene Products, Human Immunodeficiency Virus / immunology*
Substances
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AIDS Vaccines
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Epitopes
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HIV Antigens
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HIV Core Protein p24
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HLA-A Antigens
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HLA-A*03 antigen
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HLA-A3 Antigen
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HLA-B Antigens
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HLA-B57 antigen
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HSP90 Heat-Shock Proteins
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Peptide Fragments
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gag Gene Products, Human Immunodeficiency Virus
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p17 protein, Human Immunodeficiency Virus Type 1
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reverse transcriptase, Human immunodeficiency virus 1
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HIV Reverse Transcriptase
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HDAC6 protein, human
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Histone Deacetylase 6
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Histone Deacetylases