PMID- 25781895 OWN - NLM STAT- MEDLINE DCOM- 20150731 LR - 20201217 IS - 1553-7374 (Electronic) IS - 1553-7366 (Print) IS - 1553-7366 (Linking) VI - 11 IP - 3 DP - 2015 Mar TI - Variable processing and cross-presentation of HIV by dendritic cells and macrophages shapes CTL immunodominance and immune escape. PG - e1004725 LID - 10.1371/journal.ppat.1004725 [doi] LID - e1004725 AB - Dendritic cells (DCs) and macrophages (Mos) 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 Mos. The cross-presentation of HIV proteins by both DCs and Mos 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 Mo 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. FAU - Dinter, Jens AU - Dinter J AD - Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America. FAU - Duong, Ellen AU - Duong E AD - Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America. FAU - Lai, Nicole Y AU - Lai NY AD - Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America. FAU - Berberich, Matthew J AU - Berberich MJ AD - Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America. FAU - Kourjian, Georgio AU - Kourjian G AD - Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America. FAU - Bracho-Sanchez, Edith AU - Bracho-Sanchez E AD - Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America. FAU - Chu, Duong AU - Chu D AD - Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America. FAU - Su, Hang AU - Su H AD - Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America. FAU - Zhang, Shao Chong AU - Zhang SC AD - Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America. FAU - Le Gall, Sylvie AU - Le Gall S AD - Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America. LA - eng GR - R01 AI084106/AI/NIAID NIH HHS/United States GR - R01 AI084753/AI/NIAID NIH HHS/United States GR - R01 AI112493/AI/NIAID NIH HHS/United States GR - R21 AI060502/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150317 PL - United States TA - PLoS Pathog JT - PLoS pathogens JID - 101238921 RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (Immunodominant Epitopes) SB - IM MH - Cross-Priming/*immunology MH - Dendritic Cells/*immunology MH - Epitopes, T-Lymphocyte/immunology MH - HIV Infections/immunology MH - HIV-1/*immunology MH - Humans MH - Immune Evasion/*immunology MH - Immunodominant Epitopes/immunology MH - Macrophages/*immunology MH - Mass Spectrometry MH - T-Lymphocytes, Cytotoxic/*immunology PMC - PMC4364612 COIS- The authors have declared that no competing interests exist. EDAT- 2015/03/18 06:00 MHDA- 2015/08/01 06:00 PMCR- 2015/03/17 CRDT- 2015/03/18 06:00 PHST- 2014/11/02 00:00 [received] PHST- 2015/02/03 00:00 [accepted] PHST- 2015/03/18 06:00 [entrez] PHST- 2015/03/18 06:00 [pubmed] PHST- 2015/08/01 06:00 [medline] PHST- 2015/03/17 00:00 [pmc-release] AID - PPATHOGENS-D-14-02631 [pii] AID - 10.1371/journal.ppat.1004725 [doi] PST - epublish SO - PLoS Pathog. 2015 Mar 17;11(3):e1004725. doi: 10.1371/journal.ppat.1004725. eCollection 2015 Mar.