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.
Copyright © 2016 American Society for Microbiology.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, N.I.H., Extramural
MeSH terms
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Antimalarials / pharmacology*
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Aspartic Acid Endopeptidases / genetics
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Aspartic Acid Endopeptidases / metabolism
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Drug Resistance / drug effects*
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Drug Resistance / genetics
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Erythrocytes / drug effects
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Erythrocytes / parasitology
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Gene Expression
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Genome*
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HIV Protease Inhibitors / pharmacology
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High-Throughput Nucleotide Sequencing
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Humans
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Inhibitory Concentration 50
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Lopinavir / pharmacology*
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Multidrug Resistance-Associated Proteins / genetics*
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Multidrug Resistance-Associated Proteins / metabolism
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Mutation
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Plasmodium falciparum / drug effects*
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Plasmodium falciparum / genetics
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Plasmodium falciparum / growth & development
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Plasmodium falciparum / metabolism
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Protozoan Proteins / genetics
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Protozoan Proteins / metabolism
Substances
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Antimalarials
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HIV Protease Inhibitors
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Mdr1 protein, Plasmodium falciparum
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Multidrug Resistance-Associated Proteins
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Protozoan Proteins
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Lopinavir
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Aspartic Acid Endopeptidases
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plasmepsin