Lopinavir, an HIV-1 peptidase inhibitor, induces alteration on the lipid metabolism of Leishmania amazonensis promastigotes.

Karina M Rebello,Eduardo Caio Torres-Santos,Marta H Branquinha,Valter V Andrade-Neto,André L S Santos,Geórgia C Atella,Aline A Zuma,Maria Cristina M Motta,Claudia Regina B Gomes,Marcus Vinícius N De Souza,Claudia M D'Avila-Levy

doi:10.1017/s0031182018000823

Karina M Rebello, Eduardo Caio Torres-Santos + Show 9 more

Open Access

https://doi.org/10.1017/s0031182018000823

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Abstract

The anti-leishmania effects of HIV peptidase inhibitors (PIs) have been widely reported; however, the biochemical target and mode of action are still a matter of controversy in Leishmania parasites. Considering the possibility that HIV-PIs induce lipid accumulation in Leishmania amazonensis, we analysed the effects of lopinavir on the lipid metabolism of L. amazonensis promastigotes. To this end, parasites were treated with lopinavir at different concentrations and analysed by fluorescence microscopy and spectrofluorimetry, using a fluorescent lipophilic marker. Then, the cellular ultrastructure of treated and control parasites was analysed by transmission electron microscopy (TEM), and the lipid composition was investigated by thin-layer chromatography (TLC). Finally, the sterol content was assayed by gas chromatography-mass spectrometry (GC/MS). TEM analysis revealed an increased number of lipid inclusions in lopinavir-treated cells, which was accompanied by an increase in the lipophilic content, in a dose-dependent manner. TLC and GC-MS analysis revealed a marked increase of cholesterol-esters and cholesterol. In conclusion, lopinavir-induced lipid accumulation and affected lipid composition in L. amazonensis in a concentration-response manner. These data contribute to a better understanding of the possible mechanisms of action of this HIV-PI in L. amazonensis promastigotes. The concerted action of lopinavir on this and other cellular processes, such as the direct inhibition of an aspartyl peptidase, may be responsible for the arrested development of the parasite.

Highlights

Leishmaniasis is a tropical disease caused by an intracellular parasite of the genus Leishmania, which is transmitted by phlebotomine sand flies
In order to analyse the effect of lopinavir on leishmanial lipid content, L. amazonensis promastigotes cells were grown for 72 h in the presence of 1⁄2IC50, IC50 and 2 × IC50 concentrations of the compound
human immunodeficiency virus (HIV)-peptidase inhibitors (PIs) are targeted to the retroviral aspartyl peptidase, long-term treatment leads to important side-effects, such as insulin resistance (Hruz, 2008) and lipodystrophy (Hui, 2003; Nolan, 2003)

Summary

Introduction

Leishmaniasis is a tropical disease caused by an intracellular parasite of the genus Leishmania, which is transmitted by phlebotomine sand flies. An estimated 900 000–1.3 million new cases and 20 000–30 000 deaths occur annually (Alvar et al, 2012). Human immunodeficiency virus (HIV) infection is a major global public health problem and the prevalence is increasing worldwide. This scenario is worsened by an overlap between HIV and several infectious diseases, including leishmaniasis (Alvar et al, 2008). The number of reported coinfection cases has been increasing globally (Lindoso et al, 2016), and these patients have a higher risk of treatment failure, a higher risk of relapse and higher rates of mortality (Alvar et al, 2008)

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