Anti-HIV drugs, lopinavir/ritonavir and atazanavir, modulate innate immune response triggered by Leishmania in macrophages: The role of NF-κB and PPAR-γ Érica Alessandra Rocha Alves a,b , Marthina Gomes de Miranda a , Tatiana Karla Borges a , Kelly Grace Magalhães c , Maria Imaculada Muniz-Junqueira a, ⁎ a Laboratory of Cellular Immunology, Area of Pathology, Faculty of Medicine, University of Brasilia, Brasilia, Distrito Federal, Brazil b Laboratory of Cellular and Molecular Immunology, René Rachou Research Center, Belo Horizonte, Minas Gerais, Brazil c Laboratory of Immunology and Inflammation, Department of Cell Biology, Institute of Biology, University of Brasilia, Brasilia, Distrito Federal, Brazil abstract article info Article history: Received 18 September 2014 Received in revised form 10 December 2014 Accepted 15 December 2014 Available online 26 December 2014 Keywords: Lopinavir/ritonavir Atazanavir Leishmania Cytokines PPAR-γ RelB/NFκB 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 10 days 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 pro- duction of NO and H 2 O 2 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 mac- rophages 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 intracel- lular 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. © 2014 Elsevier B.V. All rights reserved. 1. Introduction The cruel synergism between HIV and Leishmania increases the risk of leishmaniasis development in HIV-infected individuals by several hundred-fold [1], through either decreased resistance to a new primary infection or reactivation of a previous subclinical infection [2]. At the same time, Leishmania infection promotes the clinical progression of HIV disease and the development of AIDS-defining conditions [3]. This occurs because of a synergistic detrimental effect on cellular immune response by targeting similar immune cells. CD4 + T cell depletion and/or functional impairments observed in HIV infection contribute to the proliferation and spread of Leishmania parasites, reduce the likelihood of a therapeutic response and greatly increase the probability of relapse [4]. In addition, the chronic immune activation determined by Leishmania infection generates the intracellular signaling necessary to HIV replication and, consequently, increases viral load and a more rapid progression to AIDS, which reduce life expectancy in HIV- infected individuals [4]. The introduction of highly active antiretroviral therapy has changed the clinical course of HIV infection and its associated illnesses [2]. How- ever, prevention of leishmaniasis relapses remains a challenge in the care of HIV and Leishmania co-infected individuals [2]. Between 38 and 70% of co-infected individuals who received highly active antiretro- viral therapy (HAART) relapsed during the 24 month-period following anti-Leishmania treatment. Relapses occurred independently of an in- crease in the number of CD4 + T cells and even with an undetectable viral load. However, it should be observed that HAART treatment improved the evolution of co-infection because the average time of relapses was 7 months longer in patients who had received HAART than in those who had not received it [5]. Nevertheless, recovery of the immune system related to HAART was also associated with International Immunopharmacology 24 (2015) 314–324 ⁎ Corresponding author at: Laboratory of Cellular Immunology, Pathology, Faculty of Medicine, University of Brasilia, Campus Darcy Ribeiro, Asa Norte, Brasilia, DF 70.910- 900, Brazil. Tel./fax: +55 61 3273 3907. E-mail addresses: erica.alves@cpqrr.fiocruz.br (É.A.R. Alves), marthina.gomes@gmail.com (M.G. de Miranda), tatianakarlab@gmail.com (T.K. Borges), kellymagalhaes@unb.br (K.G. Magalhães), mimjunqueira@unb.br, mimjunqueira@yahoo.com.br (M.I. Muniz-Junqueira). http://dx.doi.org/10.1016/j.intimp.2014.12.025 1567-5769/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp