Abstract
Dendritic cells (DCs) and macrophages (Møs) internalize and process exogenous HIV-derived antigens for cross-presentation by MHC-I to cytotoxic CD8+ T cells (CTL). However, how degradation patterns of HIV antigens in the cross-presentation pathways affect immunodominance and immune escape is poorly defined. Here, we studied the processing and cross-presentation of dominant and subdominant HIV-1 Gag-derived epitopes and HLA-restricted mutants by monocyte-derived DCs and Møs. The cross-presentation of HIV proteins by both DCs and Møs led to higher CTL responses specific for immunodominant epitopes. The low CTL responses to subdominant epitopes were increased by pretreatment of target cells with peptidase inhibitors, suggestive of higher intracellular degradation of the corresponding peptides. Using DC and Mø cell extracts as a source of cytosolic, endosomal or lysosomal proteases to degrade long HIV peptides, we identified by mass spectrometry cell-specific and compartment-specific degradation patterns, which favored the production of peptides containing immunodominant epitopes in all compartments. The intracellular stability of optimal HIV-1 epitopes prior to loading onto MHC was highly variable and sequence-dependent in all compartments, and followed CTL hierarchy with immunodominant epitopes presenting higher stability rates. Common HLA-associated mutations in a dominant epitope appearing during acute HIV infection modified the degradation patterns of long HIV peptides, reduced intracellular stability and epitope production in cross-presentation-competent cell compartments, showing that impaired epitope production in the cross-presentation pathway contributes to immune escape. These findings highlight the contribution of degradation patterns in the cross-presentation pathway to HIV immunodominance and provide the first demonstration of immune escape affecting epitope cross-presentation.
Highlights
Cytotoxic CD8+ T cell (CTL) responses play an important role in the outcome of viral infections
We compared the degradation of HIV proteins in subcellular compartments of dendritic cells and macrophages, two cell types targeted by HIV and the subsequent presentation of epitopes to T cells
We show variable degradation patterns of HIV according to compartments, and the preferential production and superior intracellular stability of immunodominant epitopes corresponding to stronger T cell responses
Summary
Cytotoxic CD8+ T cell (CTL) responses play an important role in the outcome of viral infections. The acute phase of HIV infection is characterized by narrow immunodominance patterns [2,3], and immune pressure leading to frequent escape mutations in immunodominant epitopes changes the T cell response hierarchy during disease progression [4,5,6,7,8,9]. Immunodominance is shaped by multiple factors [10], including binding affinity to MHC or the TCR [11,12], frequency of CD8+ T cell precursors and the TCR repertoire [13], kinetics of expression and amount of viral proteins [14], and efficiency of antigen processing [15,16,17]. How degradation patterns during cross-presentation of antigens, in the case of highly variable pathogens like HIV, may shape immunodominance and viral evolution is not well understood. Internalized antigens first undergo proteolytic processing by cathepsins in endocytic compartments [27] where they can be loaded onto MHC I or MHC II molecules for presentation to CD8+ or CD4+ T cells [28], or eventually escape into the cytosol [29] for additional degradation [30,31], translocation in the ER and cross-presentation by MHC I
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