The modulation of cathepsin activities by HIV protease inhibitors alters the processing and cross-presentation of pathogens

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. Pathogen uptake in phagosomes initiates infection of macrophages and leads to the priming of T cell responses by dendritic cells. The original degradation of antigens is performed by pH-dependent endolysosomal cathepsins. We show that HIV protease inhibitors (PIs) prescribed to HIV-infected persons variably modulate cathepsin hydrolytic activities in human antigen presenting cells (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 activities: They directly enhanced procathepsin maturation and increased cathepsin hydrolytic activities. They indirectly altered regulators of cathepsin functions by inhibiting Akt kinase activities, reducing NADPH oxidase 2 (NOX2) activation, lowering phagolysosomal ROS production and pH, which altogether 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 antigens by dendritic cells and epitope-specific T cell-mediated killing by up to 2.5-fold. HIV PI-induced modulation of antigen processing partly changed the self MHC-peptidome displayed by primary human cells. This first identification 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.