Altered Plasmodium falciparum Sensitivity to the Antiretroviral Protease Inhibitor Lopinavir Associated with Polymorphisms in pfmdr1.
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.
Department of Medicine, University of California, San Francisco, California, USA.
Ebere
E
Sonoiki
Department of Medicine, University of California, San Francisco, California, USA.
Christian
C
Nsanzabana
Department of Medicine, University of California, San Francisco, California, USA.
Jennifer
J
Legac
Department of Medicine, University of California, San Francisco, California, USA.
Kirthana M V
KM
Sindhe
Howard Hughes Medical Institute and the Department of Biochemistry and Biophysics, University of California, San Francisco, California, USA.
Joseph
0000-0002-4611-9205
J
DeRisi
Department of Medicine, University of California, San Francisco, California, USA philip.rosenthal@ucsf.edu.
Philip J
PJ
Rosenthal
D000962:Antimalarials / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance / Q000187:drug effects* / Q000235:genetics; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D015870:Gene Expression; D016678:Genome; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020128:Inhibitory Concentration 50; D061466:Lopinavir / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism
D000962:Antimalarials; D016282:Aspartic Acid Endopeptidases; D017320:HIV Protease Inhibitors; D061466:Lopinavir; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; C513498:Mdr1 protein, Plasmodium falciparum; C089643:plasmepsin
HIV; Plasmodium falciparum; antiretroviral; aspartic protease; drug resistance; drug resistance mechanisms; drug sensitivity; lopinavir; malaria; pfmdr1