Pharmacol Ther. 2011 Dec;132(3):268-79. doi: 10.1016/j.pharmthera.2011.06.007. Epub 2011 Jul 23.
Drug uptake transporters in antiretroviral therapy
Gerard Minuesa 1, Isabel Huber-Ruano, Marçal Pastor-Anglada, Hermann Koepsell, Bonaventura Clotet, Javier Martinez-Picado
Current treatment of human immunodeficiency virus-1 (HIV-1) infection is effective, although it does not permanently suppress viral replication in all patients. Viral persistence, drug toxicity, and antiretroviral resistance are challenging barriers to successful treatment of HIV-1 infection. It has become increasingly apparent that the balance between drug influx and efflux transporter activity plays a critical role in the overall disposition of anti-HIV drugs in both cells and tissues. Thus, drug transporters directly influence the appearance of drug resistance and toxicity, and could also be related to persistence of HIV-1. We review the role of drug uptake transporters from the solute carrier (SLC) superfamily, their relation with specific antiretroviral drug disposition, and their efficacy in the tissues that absorb, metabolize, and eliminate anti-HIV drugs. Recent studies focusing on the role of drug uptake transporters in immune cells, key sites in the action of antiviral therapy, are highlighted.
Trends Pharmacol Sci. 2010 Jan;31(1):22-35. doi: 10.1016/j.tips.2009.10.001. Epub 2009 Dec 11.
The complexities of antiretroviral drug-drug interactions: role of ABC and SLC transporters
Olena Kis 1, Kevin Robillard, Gary N Y Chan, Reina Bendayan
Treatment of human immunodeficiency virus (HIV) infection involves a combination of several antiviral agents belonging to different pharmacological classes. This combination is referred to as highly active antiretroviral therapy (HAART). This treatment has proved to be very effective in suppressing HIV replication, but antiretroviral drugs have complex pharmacokinetic properties involving extensive drug metabolism and transport by membrane-associated drug carriers. Combination drug therapy often introduces complex drug-drug interactions that can result in toxic or sub-therapeutic drug concentrations, compromising treatment. This review focuses on the role of ATP-binding cassette (ABC) membrane-associated efflux transporters and solute carrier (SLC) uptake transporters in antiretroviral drug disposition, and identifies clinically important antiretroviral drug-drug interactions associated with changes in drug transport.
Adv Drug Deliv Rev. 2016 Aug 1;103:121-143. doi: 10.1016/j.addr.2016.05.001. Epub 2016 May 13.
Role and modulation of drug transporters in HIV-1 therapy
Camille Alam 1, Sana-Kay Whyte-Allman 1, Amila Omeragic 1, Reina Bendayan 2
Current treatment of human immunodeficiency virus type-1 (HIV-1) infection involves a combination of antiretroviral drugs (ARVs) that target different stages of the HIV-1 life cycle. This strategy is commonly referred to as highly active antiretroviral therapy (HAART) or combined antiretroviral therapy (cART). Membrane-associated drug transporters expressed ubiquitously in mammalian systems play a crucial role in modulating ARV disposition during HIV-1 infection. Members of the ATP-binding cassette (ABC) and solute carrier (SLC) transporter superfamilies have been shown to interact with ARVs, including those that are used as part of first-line treatment regimens. As a result, the functional expression of drug transporters can influence the distribution of ARVs at specific sites of infection. In addition, pathological factors related to HIV-1 infection and/or ARV therapy itself can alter transporter expression and activity, thus further contributing to changes in ARV disposition and the effectiveness of HAART. This review summarizes current knowledge on the role of drug transporters in regulating ARV transport in the context of HIV-1 infection.
J Antimicrob Chemother. 2011 Apr;66(4):802-12. doi: 10.1093/jac/dkq501. Epub 2011 Jan 19.
Potential of novel antiretrovirals to modulate expression and function of drug transporters in vitro
Nadine Cécile Luise Zembruski 1, Gabriele Büchel, Lisa Jödicke, Melanie Herzog, Walter Emil Haefeli, Johanna Weiss
Objectives: The chemokine receptor antagonists maraviroc and vicriviroc and the integrase inhibitors elvitegravir and raltegravir are novel antiretroviral agents for the treatment of HIV-1 infections. ATP-binding cassette (ABC) transporters as modulators of the effectiveness and safety of therapy can mediate viral resistance and drug-drug interactions. To expand knowledge on drug-drug interactions of these antiretrovirals we investigated whether these compounds are substrates, inhibitors or inducers of important ABC transporters.
Methods: We evaluated P-glycoprotein (P-gp/ABCB1) inhibition by the calcein assay in P388/dx and L-MDR1 cells, breast cancer resistance protein (BCRP/ABCG2) inhibition in MDCKII-BCRP cells by pheophorbide A efflux, and inhibition of the multidrug resistance-associated protein 2 (MRP2/ABCC2) by using the MRP2 PREDIVEZ™ Vesicular Transport Kit. Substrate characteristics were evaluated by growth inhibition assays in MDCKII cells overexpressing particular ABC transporters. Induction of transporters was quantified by real-time RT-PCR in LS180 cells and for ABCB1 also at the functional level.
Results: Elvitegravir and vicriviroc inhibited ABCB1 in P388/dx and L-MDR1 cells (f2 values 1.9±0.2 µmol/L and 8.5±3.6 µmol/L, respectively). The IC50 for ABCG2 inhibition was 15.7±5.7 µmol/L for elvitegravir and 236.7±93.3 µmol/L for vicriviroc. Raltegravir and maraviroc showed no evidence of ABCB1 or ABCG2 inhibition. Maraviroc and vicriviroc stimulated ABCC2 transport function. Growth inhibition assays suggest that elvitegravir, raltegravir and vicriviroc are substrates of ABCB1. Induction assays demonstrate that mRNA expression of several ABC transporters is induced by these antiretrovirals in LS180 cells.
Conclusions: The new antiretrovirals bear the potential to modulate expression and function of several ABC transporters, with elvitegravir revealing the highest interaction potential.
PLoS One. 2014; 9(3): e92140.
Up-Regulation of the ATP-Binding Cassette Transporter A1 Inhibits Hepatitis C Virus Infection
Simone Bocchetta,# 1 , 2 Patrick Maillard,# 1 Mami Yamamoto,# 1 , 3 Claire Gondeau, 4 Florian Douam, 5 Stéphanie Lebreton, 6 Sylvie Lagaye, 7 Stanislas Pol, 7 , 8 François Helle, 9 Wanee Plengpanich, 10 , 11 Maryse Guérin, 10 Maryline Bourgine, 12 Marie Louise Michel, 12 Dimitri Lavillette, 5 Philippe Roingeard, 13 Wilfried le Goff, 10 and Agata Budkowska 1 , *
Hepatitis C virus (HCV) establishes infection using host lipid metabolism pathways that are thus considered potential targets for indirect anti-HCV strategies. HCV enters the cell via clathrin-dependent endocytosis, interacting with several receptors, and virus-cell fusion, which depends on acidic pH and the integrity of cholesterol-rich domains of the hepatocyte membrane. The ATP-binding Cassette Transporter A1 (ABCA1) mediates cholesterol efflux from hepatocytes to extracellular Apolipoprotein A1 and moves cholesterol within cell membranes. Furthermore, it generates high-density lipoprotein (HDL) particles. HDL protects against arteriosclerosis and cardiovascular disease. We show that the up-regulation of ABCA1 gene expression and its cholesterol efflux function in Huh7.5 hepatoma cells, using the liver X receptor (LXR) agonist GW3965, impairs HCV infection and decreases levels of virus produced. ABCA1-stimulation inhibited HCV cell entry, acting on virus-host cell fusion, but had no impact on virus attachment, replication, or assembly/secretion. It did not affect infectivity or properties of virus particles produced. Silencing of the ABCA1 gene and reduction of the specific cholesterol efflux function counteracted the inhibitory effect of the GW3965 on HCV infection, providing evidence for a key role of ABCA1 in this process. Impaired virus-cell entry correlated with the reorganisation of cholesterol-rich membrane microdomains (lipid rafts). The inhibitory effect could be reversed by an exogenous cholesterol supply, indicating that restriction of HCV infection was induced by changes of cholesterol content/distribution in membrane regions essential for virus-cell fusion. Stimulation of ABCA1 expression by GW3965 inhibited HCV infection of both human primary hepatocytes and isolated human liver slices. This study reveals that pharmacological stimulation of the ABCA1-dependent cholesterol efflux pathway disrupts membrane cholesterol homeostasis, leading to the inhibition of virus–cell fusion and thus HCV cell entry. Therefore besides other beneficial roles, ABCA1 might represent a potential target for HCV therapy.