title: Low-density lipoprotein and ritonavir: an interaction between antiretrovirals and lipids mediated by P-glycoprotein.
abstract: BACKGROUND
  Antiretroviral therapy has considerably reduced HIV disease progression, but complete eradication of HIV cannot actually be achieved. Moreover, prolonged use of protease inhibitors (PIs) causes profound changes in lipid metabolism with an increased risk of cardiovascular diseases. P-glycoprotein (P-gp) is expressed on many cell types, playing an important role in the efflux of drugs including PIs, limiting their intracellular concentration. Furthermore, several studies showed that P-gp is involved in lipid homeostasis and its activity is regulated by cholesterol.
  
  
  METHODS
  THP-1 monocytes were used to study: (i) the influence of low-density lipoprotein (LDL) on P-gp expression and function, assessed by flow cytometry and quantitative real-time PCR analysis and measuring ritonavir and rhodamine-123 dye efflux, respectively; and (ii) the influence of ritonavir on cholesterol mobilization. The intracellular levels of ritonavir or cholesterol were measured by HPLC-UV and filipin staining, respectively.
  
  
  RESULTS
  In THP-1 cells, LDL was able to yield an increase in both P-gp expression and activity. THP-1 cells treated with 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-gp activity.
  
  
  CONCLUSIONS
  Our data indicate a potential interplay between LDL and ritonavir mediated by P-gp. This interaction could influence both therapy effectiveness and cellular lipid metabolism, with important implications in the management of HIV patients treated with boosted PIs.
authors.affiliation: Clinical Biochemistry and Pharmacology Laboratory, National Institute for Infectious Diseases, 'L. Spallanzani' IRCCS, Via Portuense, 292, 00149 Rome, Italy massimo.tempestilli@inmi.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Tempestilli
authors.affiliation: Clinical Biochemistry and Pharmacology Laboratory, National Institute for Infectious Diseases, 'L. Spallanzani' IRCCS, Via Portuense, 292, 00149 Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Elisei
authors.affiliation: Cellular Immunology Laboratory, National Institute for Infectious Diseases, 'L. Spallanzani' IRCCS, Via Portuense, 292, 00149 Rome, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Cimini
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, C.so Svizzera 164, 10149 Torino, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Avolio
authors.affiliation: Gene Expression and Experimental Hepatology Laboratory, National Institute for Infectious Diseases, 'L. Spallanzani' IRCCS, Via Portuense, 292, 00149 Rome, Italy.
authors.forename: Germana
authors.initials: G
authors.lastname: Grassi
authors.affiliation: Clinical Department, National Institute for Infectious Diseases, 'L. Spallanzani' IRCCS, Via Portuense, 292, 00149 Rome, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Nicastri
authors.affiliation: Clinical Department, National Institute for Infectious Diseases, 'L. Spallanzani' IRCCS, Via Portuense, 292, 00149 Rome, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Narciso
authors.affiliation: Cellular Immunology Laboratory, National Institute for Infectious Diseases, 'L. Spallanzani' IRCCS, Via Portuense, 292, 00149 Rome, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Martini
authors.affiliation: Gene Expression and Experimental Hepatology Laboratory, National Institute for Infectious Diseases, 'L. Spallanzani' IRCCS, Via Portuense, 292, 00149 Rome, Italy.
authors.forename: Tonino
authors.initials: T
authors.lastname: Alonzi
authors.affiliation: Clinical Biochemistry and Pharmacology Laboratory, National Institute for Infectious Diseases, 'L. Spallanzani' IRCCS, Via Portuense, 292, 00149 Rome, Italy.
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Paolo Pucillo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D019380:Anti-HIV Agents / Q000378:metabolism* / Q000493:pharmacokinetics*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000737:chemistry; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D009000:Monocytes; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D019438:Ritonavir / Q000378:metabolism* / Q000493:pharmacokinetics*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D008077:Lipoproteins, LDL; D019438:Ritonavir
keywords: THP-1; multidrug resistance; protease inhibitors