Differential effects of p-glycoprotein and multidrug resistance protein-1 on productive human immunodeficiency virus infection.
P-glycoprotein (P-gp) and multidrug-resistance protein-1 (MRP-1) are adenosine triphosphate-binding cassette proteins that may decrease intracellular concentrations of anti-human immunodeficiency virus (HIV) drugs. After HIV-1(IIIB) infection, HIV-1 protein and infectious virus production were decreased by at least 70-fold in CEM cells overexpressing P-gp but were increased by at least 50-fold in CEM cells overexpressing MRP-1, compared with control CEM cells. After transfection with the HIV-1(IIIB) genome, cells overexpressing P-gp and MRP-1 expressed similar amounts of HIV protein. Selective inhibitors of MRP-1 and P-gp partially reversed the effect of these transporters in a concentration-dependent manner. P-gp preferentially associated with glycolipid-enriched membrane (GEM) domains, which may be an important site for cellular binding and egress of HIV. In contrast, MRP-1 was not preferentially found in GEM domains. These results suggest that the inhibition of HIV productive infection by P-gp and augmentation by MRP-1 occur predominantly at a preintegration step but act through different mechanisms.
Speck
R Renae
RR
Department of Clinical Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. speck@jhu.edu
Yu
Xiao-Fang
XF
Hildreth
James
J
Flexner
Charles
C
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D004279:DNA, Viral / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D019833:Genistein / Q000494:pharmacology; D006678:HIV / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D011339:Probenecid / Q000494:pharmacology; D014162:Transfection; D014700:Verapamil / Q000494:pharmacology; D014779:Virus Replication / Q000502:physiology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D004279:DNA, Viral; D004791:Enzyme Inhibitors; D014700:Verapamil; D019833:Genistein; D011339:Probenecid