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

Massimo Tempestilli, Federica Elisei, Eleonora Cimini, Antonio D'avolio, Germana Grassi, Emanuele Nicastri, Pasquale Narciso, Federico Martini, Tonino Alonzi, Leopoldo Paolo Pucillo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numberdku066
Pages (from-to)1760-1766
Number of pages7
JournalJournal of Antimicrobial Chemotherapy
Volume69
Issue number7
DOIs
Publication statusPublished - 2014

Keywords

  • Multidrug resistance
  • Protease inhibitors
  • THP-1

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases
  • Medicine(all)

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