title: Variable HIV peptide stability in human cytosol is critical to epitope presentation and immune escape.
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.
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, USA.
authors.forename: Estibaliz
authors.initials: E
authors.lastname: Lazaro
authors.forename: Carl
authors.initials: C
authors.lastname: Kadie
authors.forename: Pamela
authors.initials: P
authors.lastname: Stamegna
authors.forename: Shao Chong
authors.initials: SC
authors.lastname: Zhang
authors.forename: Pauline
authors.initials: P
authors.lastname: Gourdain
authors.forename: Nicole Y
authors.initials: NY
authors.lastname: Lai
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Martinez
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Sylvie
authors.initials: S
authors.lastname: Le Gall
mesh_terms: D016915:AIDS Vaccines; D000465:Algorithms; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D017951:Antigen Presentation; D019295:Computational Biology; D016384:Consensus Sequence; D003600:Cytosol / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D015488:HIV Antigens / Q000737:chemistry / Q000276:immunology*; D016655:HIV Core Protein p24 / Q000737:chemistry / Q000276:immunology*; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D015234:HLA-A Antigens / Q000276:immunology; D015791:HLA-A3 Antigen; D015235:HLA-B Antigens / Q000276:immunology; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology; D006207:Half-Life; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D055550:Protein Stability; D037182:T-Cell Antigen Receptor Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D000939:Epitopes; D015488:HIV Antigens; D016655:HIV Core Protein p24; D015234:HLA-A Antigens; C487960:HLA-A*03 antigen; D015791:HLA-A3 Antigen; D015235:HLA-B Antigens; C103707:HLA-B57 antigen; D018841:HSP90 Heat-Shock Proteins; D010446:Peptide Fragments; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases