Variable HIV peptide stability in human cytosol is critical to epitope presentation and immune escape
Estibaliz Lazaro, … , David Heckerman, Sylvie Le Gall
Estibaliz Lazaro, … , David Heckerman, Sylvie Le Gall
Published May 9, 2011
Citation Information: J Clin Invest. 2011;121(6):2480-2492. https://doi.org/10.1172/JCI44932.
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Research Article Virology

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

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

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Figure 2

The cytosolic stability of HIV epitopes is highly variable.

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The cytosolic stability of HIV epitopes is highly variable. (A) Distribu...
(A) Distribution of 166 optimal HIV epitopes (gray bar) across HIV proteins (black bars). (B) The stability rate of 166 epitopes was calculated by a nonlinear regression (one-phase exponential decay) of the degradation profile obtained over a 30-minute incubation in PBMC cytosol (average of >3 independent experiments with extracts from different donors). Four stability groups of epitopes were identified according to their stability rates (<0.1, 0.1–0.5, >0.5–1, >1–2, and >2) and corresponding half-life brackets (<30 seconds, 30–90 seconds, >1.5–20 minutes, >20 minutes). (C) Ratio between the percentage of epitopes in each protein in each stability bracket and the percentage of epitopes in this bracket for all proteins. *P = 0.016 and †P = 0.0129 for p17- and Protease-derived (Pro) peptides; Mann-Whitney U test. (D) Distribution of peptide stability rates according to restricting HLA alleles (protective: HLA-B27, -B51, -B57; not protective: HLA-B08 and -B35; no effect: all other 68 HLAs). Ratio between the percentage of epitopes in each stability bracket for each HLA group and the percentage of epitopes in each stability bracket for all HLAs tested. P = 0.4239 for the overall comparison between the 3 groups of HLAs (Mann-Whitney U test). The comparison between protective and nonprotective HLA alleles showed P = 0.3667 for unstable peptides (stability rate, <0.5), P = 0.1669 for intermediate peptides (0.5–1), P = 0.1777 for peptides with stability rates >1–2 minutes, and P = 0.1612 for the most stable peptides (>2).