title: Anti-HIV drugs, lopinavir/ritonavir and atazanavir, modulate innate immune response triggered by Leishmania in macrophages: the role of NF-κB and PPAR-γ.
abstract: This study evaluated the influence of HIV protease inhibitors lopinavir/ritonavir (LPV/RTV) and atazanavir (ATV) on macrophage functions during their first interaction with Leishmania. Macrophages from BALB/c mice treated for 10days with LPV/RTV and ATV, infected or not in vitro with L. (L.) amazonensis, were used to investigate the effects of these drugs on infection index, leishmanicidal capacity, cytokine production and PPAR-γ and RelB expression. LPV/RTV and ATV treatments significantly increased the infection index and the percentage of Leishmania-infected macrophages compared to untreated infected macrophages. There was no correlated increase in the production of NO and H2O2 leishmanicidal molecules. Promastigotes derived from Leishmania-infected macrophages from LPV/RTV and ATV-treated BALB/c mice had an in vitro growth 45.1% and 56.4% higher in groups treated with LPV/RTV and ATV than with PBS in culture. ATV treatment reduced IL-12p70 and IL-10 secretion in Leishmania-infected macrophages, but had no effect on IL-23 and TNF production. LPV reduced IL-10 and had no effect on IL-12p70, TNF and IL-23 secretion. ATV treatment decreased PPAR-γ expression in Leishmania-infected macrophages compared to untreated infected macrophages. In addition, LPV/RTV, but not ATV, reduced RelB cytoplasm-to-nucleus translocation in Leishmania-infected macrophages. Results showed that LPV/RTV and ATV HIV protease inhibitors were able to modulate innate defense mechanisms against Leishmania via different intracellular pathways. Although HIV protease inhibitors are highly efficient to control the Human Immunodeficiency Virus, these drugs might also influence the course of leishmaniasis in HIV-Leishmania-co-infected individuals.
authors.affiliation: Laboratory of Cellular Immunology, Area of Pathology, Faculty of Medicine, University of Brasilia, Brasilia, Distrito Federal, Brazil; Laboratory of Cellular and Molecular Immunology, René Rachou Research Center, Belo Horizonte, Minas Gerais, Brazil. Electronic address: erica.alves@cpqrr.fiocruz.br.
authors.forename: Érica Alessandra Rocha
authors.initials: ÉAR
authors.lastname: Alves
authors.affiliation: Laboratory of Cellular Immunology, Area of Pathology, Faculty of Medicine, University of Brasilia, Brasilia, Distrito Federal, Brazil. Electronic address: marthina.gomes@gmail.com.
authors.forename: Marthina Gomes
authors.initials: MG
authors.lastname: de Miranda
authors.affiliation: Laboratory of Cellular Immunology, Area of Pathology, Faculty of Medicine, University of Brasilia, Brasilia, Distrito Federal, Brazil. Electronic address: tatianakarlab@gmail.com.
authors.forename: Tatiana Karla
authors.initials: TK
authors.lastname: Borges
authors.affiliation: Laboratory of Immunology and Inflammation, Department of Cell Biology, Institute of Biology, University of Brasilia, Brasilia, Distrito Federal, Brazil. Electronic address: kellymagalhaes@unb.br.
authors.forename: Kelly Grace
authors.initials: KG
authors.lastname: Magalhães
authors.affiliation: Laboratory of Cellular Immunology, Area of Pathology, Faculty of Medicine, University of Brasilia, Brasilia, Distrito Federal, Brazil. Electronic address: mimjunqueira@unb.br.
authors.forename: Maria Imaculada
authors.initials: MI
authors.lastname: Muniz-Junqueira
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000069446:Atazanavir Sulfate / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects; D007891:Leishmania / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D007896:Leishmaniasis / Q000276:immunology* / Q000469:parasitology; D061466:Lopinavir / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology / Q000469:parasitology; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000276:immunology*; D009573:Nitrites / Q000276:immunology; D047495:PPAR gamma / Q000276:immunology*; D019438:Ritonavir / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D016207:Cytokines; D016328:NF-kappa B; D009573:Nitrites; D047495:PPAR gamma; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D006861:Hydrogen Peroxide; D019438:Ritonavir
keywords: Atazanavir; Cytokines; Leishmania; Lopinavir/ritonavir; PPAR-γ; RelB/NFκB