Details

Autor(en) / Beteiligte

• Zhang, Shao Chong
• Martin, Eric
• Shimada, Mariko
• Godfrey, Sasha Blue
• Fricke, Jennifer
• Locastro, Shirley
• Lai, Nicole Y.
• Liebesny, Paul
• Carlson, Jonathan M.
• Brumme, Chanson J.
• Ogbechie, Oluwatobi Awele
• Chen, Huabiao
• Walker, Bruce D.
• Brumme, Zabrina L.
• Kavanagh, Daniel G.
• Le Gall, Sylvie

Titel

Aminopeptidase Substrate Preference Impacts HIV Epitope Presentation and Predicts Immune Escape Patterns in HIV-infected Persons

Ist Teil von

• The Journal of immunology (1950), 2012-05, Vol.188 (12), p.5924-5934

Erscheinungsjahr

2012

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Viruses evade immune detection partly through immune-associated mutations. Analyses of HIV sequences derived from infected persons have identified numerous examples of HLA-associated mutations within or adjacent T cell epitopes, but the potential impact of most mutations on epitope production and presentation remains unclear. The multistep breakdown of proteins into epitopes includes trimming of N-extended peptides into epitopes by aminopeptidases before loading onto MHC-I molecules. Defining sequence signatures that modulate epitope production would lead to a better understanding of factors driving viral evolution and immune escape at the population level. Here we identified cytosolic aminopeptidases cleavage preferences in primary cells, its impact on HIV antigen degradation into epitopes in primary human cell extracts by mass spectrometry, and on epitope presentation to CTL. We observed a hierarchy of preferred amino acid cleavage by cytosolic aminopeptidases. We demonstrated that flanking mutations producing more or less cleavable motifs can increase or decrease epitope production and presentation by up to 14-fold. We found that the efficiency of epitope production correlates with cleavability of flanking residues. These in vitro findings were supported by in vivo population-level analyses of clinically-derived viral sequences from 1134 antiretroviral-naïve HIV-infected persons: HLA-associated mutations immune pressures drove the selection of residues that are less cleavable by aminopeptidases predominantly at N-flanking sites, leading to reduced epitope production and immune recognition. These results underscore an important and widespread role of antigen processing mutations in HIV immune escape and identify molecular mechanisms underlying impaired epitope presentation.