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Vascular endothelial cells from different tissues express functional MDR‐1 (P‐gp) and MRP membrane transporters which efflux HIV‐1 protease inhibitors: possible role in persistence of perivascular reservoirs of HIV‐1
Author(s) -
Mondal Debasis,
Eilers Mark
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1127
Subject(s) - efflux , p glycoprotein , multidrug resistance associated proteins , transporter , atp binding cassette transporter , multiple drug resistance , saquinavir , biology , calcein , intracellular , multidrug resistance associated protein 2 , pharmacology , microbiology and biotechnology , biochemistry , immunology , human immunodeficiency virus (hiv) , membrane , gene , antiretroviral therapy , viral load , antibiotics
The HIV‐1 protease inhibitors (PIs) have significantly decreased AIDS mortality. However, due to viral propagation in sequestered reservoirs generation of PI resistant strains can occur rapidly. The multidrug resistant‐1 (MDR‐1) and multidrug resistance‐associated protein (MRP) membrane transporters expressed on brain endothelial cells (ECs) are known to efflux PIs. We monitored whether ECs obtained from a number of other vascular beds may also express efflux transporters, and documented their contribution towards decreasing intracellular levels of PIs. Primary human ECs obtained from, aortas (HAEC), pulmonary arteries (HPAECs), umbilical veins (HUVECs), dermal microvessels (DMVECs), and brain microvessels (BMVECs), were used in these in vitro studies. Gene expression for MDR‐1 and MRP‐1 & MRP‐2 was monitored by RT‐PCR, and their protein levels were determined by western immunodetection. Efflux function was monitored by determining intracellular levels of calcein (a fluorescent MDR‐1 and MRP substrate) and PI‐efflux was determined by using 3 H‐saquinavir (a PI). Pharmacologic blockers of MDR‐1 (e.g. verapamil) and MRP (e.g. MK‐571); were used to suppress transporter specific efflux function. We documented functional expression of both MDR‐1 and MRP‐1/2 in all of the EC types tested, however, a differential contribution of each transporter was seen in PI‐efflux from each EC population. These observations suggested that both large vessel and microvessel ECs may actively efflux HIV‐1 PIs via MDR‐1 and MRP. The level of expression of these transporters may dictate PI concentrations in perivascular sanctuaries of HIV‐1.