Details

Autor(en) / Beteiligte

• Lazaro, Estibaliz
• Kadie, Carl
• Stamegna, Pamela
• Zhang, Shao Chong
• Gourdain, Pauline
• Lai, Nicole Y
• Zhang, Mei
• Martinez, Sergio A
• Heckerman, David
• Le Gall, Sylvie

Titel

Variable HIV peptide stability in human cytosol is critical to epitope presentation and immune escape

Ist Teil von

• The Journal of clinical investigation, 2011-06, Vol.121 (6), p.2480-2492

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2011

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.