Altered Plasmodium falciparum Sensitivity to the Antiretroviral Protease Inhibitor Lopinavir Associated with Polymorphisms in pfmdr1 - PubMed (original) (raw)

Altered Plasmodium falciparum Sensitivity to the Antiretroviral Protease Inhibitor Lopinavir Associated with Polymorphisms in pfmdr1

Ebere Sonoiki et al. Antimicrob Agents Chemother. 2016.

Abstract

The HIV protease inhibitor lopinavir inhibits Plasmodium falciparum aspartic proteases (plasmepsins) and parasite development, and children receiving lopinavir-ritonavir experienced fewer episodes of malaria than those receiving other antiretroviral regimens. Resistance to lopinavir was selected in vitro over ∼9 months, with ∼4-fold decreased sensitivity. Whole-genome sequencing of resistant parasites showed a mutation and increased copy number in pfmdr1 and a mutation in a protein of unknown function, but no polymorphisms in plasmepsin genes.

Keywords: HIV; Plasmodium falciparum; antiretroviral; aspartic protease; drug resistance; drug resistance mechanisms; drug sensitivity; lopinavir; malaria; pfmdr1.

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Figures

FIG 1

Selection of P. falciparum with decreased sensitivity to lopinavir. Each selection from wild type (WT) to generations R1 to R4 is indicated by an arrow, with the selection concentration and time indicated. Sensitivities of selected strains are shown (50% inhibitory concentration [IC50]; mean of triplicate measures ± standard error of the mean [SEM]). WT sensitivity is the mean of assessments at each time point for cultures grown in parallel without lopinavir. Polymorphisms in R3 and R4 parasites are shown. The copy numbers of PFE1150w were 1 in WT and 4 in R3 and R4 parasites.

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Altered Plasmodium falciparum Sensitivity to the Antiretroviral Protease Inhibitor Lopinavir Associated with Polymorphisms in pfmdr1 - PubMed (original) (raw)