The effect of antiretrovirals on Plasmodium falciparum liver stages

Abstract

HIV and malaria overlap geographically, but the full impact of different antiretrovirals on malaria remains poorly understood. We examined the antimalarial activity of the HIV protease inhibitors lopinavir and saquinavir and the non-nucleoside reverse transcriptase inhibitor nevirapine on Plasmodium falciparum liver stages. Our results demonstrate that the HIV PI lopinavir inhibits liver stage parasites at clinically relevant concentrations, that is, at drug levels achieved in HIV-infected patients on standard dosing regimens. Because drugs that inhibit liver stages target parasites when they are present in lower numbers, these results might have implications for eradication efforts.

Figure 1. HIV PIs and NNRTIs inhibit Plasmodium falciparum liver stage parasites (exoerythrocytic forms/EEFs) at the high end of clinically relevant concentrations

P. falciparum sporozoites were seeded onto monolayers of HC04 cells and incubated in the presence of indicated ARTs (lopinavir, LPV; saquinavir, SAQ; nevirapine, NVP) at the indicated concentrations. On day 4, cells were fixed and stained with a monoclonal antibody specific for Plasmodium HSP70 and counted on an epifluorescence microscope. Shown are the combined results from 2 independent experiments, with horizontal lines indicating the mean. Statistics were performed using Kruskal-Wallis with Dunn’s post-test on combined experiments values to identify statistically significant differences between treated and control. All values were normalized to DMSO control and expressed as percent of DMSO control. No significant differences were detected between DMSO control and infectivity controls (cell medium only). Three stars indicate p< .001, two stars indicate p<0.01. For EEF number, significant differences were found between treated and control groups at the highest doses only for each ART tested (lopinavir and saquinavir each compared to control, p<0.001; nevirapine, p<0.01). Only lopinavir significantly inhibited EEF development at clinically relevant concentrations.