title: HIV Protease Inhibitor-Induced Cathepsin Modulation Alters Antigen Processing and Cross-Presentation.
abstract: Immune recognition by T cells relies on the presentation of pathogen-derived peptides by infected cells, but the persistence of chronic infections calls for new approaches to modulate immune recognition. Ag cross-presentation, the process by which pathogen Ags are internalized, degraded, and presented by MHC class I, is crucial to prime CD8 T cell responses. The original degradation of Ags is performed by pH-dependent endolysosomal cathepsins. In this article, we show that HIV protease inhibitors (PIs) prescribed to HIV-infected persons variably modulate cathepsin activities in human APCs, dendritic cells and macrophages, and CD4 T cells, three cell subsets infected by HIV. Two HIV PIs acted in two complementary ways on cathepsin hydrolytic activities: directly on cathepsins and indirectly on their regulators by inhibiting Akt kinase activities, reducing NADPH oxidase 2 activation, and lowering phagolysosomal reactive oxygen species production and pH, which led to enhanced cathepsin activities. HIV PIs modified endolysosomal degradation and epitope production of proteins from HIV and other pathogens in a sequence-dependent manner. They altered cross-presentation of Ags by dendritic cells to epitope-specific T cells and T cell-mediated killing. HIV PI-induced modulation of Ag processing partly changed the MHC self-peptidome displayed by primary human cells. This first identification, to our knowledge, of prescription drugs modifying the regulation of cathepsin activities and the MHC-peptidome may provide an alternate therapeutic approach to modulate immune recognition in immune disease beyond HIV.
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139.
authors.forename: Georgio
authors.initials: G
authors.lastname: Kourjian
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139.
authors.forename: Marijana
authors.initials: M
authors.lastname: Rucevic
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139.
authors.forename: Matthew J
authors.identifier: 0000-0003-2196-3757
authors.initials: MJ
authors.lastname: Berberich
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139.
authors.forename: Jens
authors.initials: J
authors.lastname: Dinter
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wambua
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139.
authors.forename: Julie
authors.initials: J
authors.lastname: Boucau
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139 sylvie_legall@hms.harvard.edu.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Le Gall
mesh_terms: D017951:Antigen Presentation / Q000187:drug effects*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000821:virology; D002403:Cathepsins / Q000378:metabolism*; D045142:Cross-Priming / Q000187:drug effects*; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000821:virology; D011992:Endosomes / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D018984:Epitopes, T-Lymphocyte / Q000187:drug effects / Q000276:immunology; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000821:virology; D008562:Membrane Glycoproteins / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018984:Epitopes, T-Lymphocyte; D017320:HIV Protease Inhibitors; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D002403:Cathepsins