Low-density lipoprotein and ritonavir: an interaction between antiretrovirals and lipids mediated by P-glycoprotein

Received 30 October 2013; returned 17 December 2013; revised 11 February 2014; accepted 17 February 2014Background: Antiretroviral therapy has considerably reduced HIVdisease progression, but complete eradicationofHIVcannotactuallybeachieved.Moreover,prolongeduseofproteaseinhibitors(PIs)causesprofoundchangesin lipidmetabolismwith an increased riskofcardiovasculardiseases. P-glycoprotein(P-gp)is expressedonmanycell types, playing an important role in the efflux of drugs including PIs, limiting their intracellularconcentration.Furthermore, several studies showed that P-gp is involved in lipid homeostasis and its activity is regulated bycholesterol.Methods: THP-1 monocytes wereused to study: (i) the influence of low-density lipoprotein(LDL) on P-gpexpres-sion and function, assessed by flow cytometry and quantitative real-time PCR analysis and measuring ritonavirand rhodamine-123 dye efflux, respectively; and (ii) the influence of ritonavir on cholesterol mobilization. Theintracellular levels of ritonavir or cholesterol were measured by HPLC-UVand filipin staining, respectively.Results: InTHP-1 cells, LDLwas able toyield an increase inbothP-gpexpression and activity. THP-1 cellstreatedwith LDL showed a decrease in the intracellular ritonavir concentration in a dose-dependent manner. Notably,ritonavir induced reduced cholesterol mobilization in THP-1 cells, probably due to its inhibitory action on P-gpactivity.Conclusions:OurdataindicateapotentialinterplaybetweenLDLandritonavirmediatedbyP-gp.Thisinteractioncouldinfluenceboththerapyeffectivenessandcellularlipidmetabolism,withimportantimplicationsintheman-agement of HIV patients treated with boosted PIs.Keywords: multidrug resistance, protease inhibitors, THP-1