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ORIGINAL RESEARCH ARTICLE

Ritonavir Increases CD36, ABCA1 and CYP27 Expression in THP-1 Macrophages

Jordi Pou^*, Alba Rebollo^*, Núria Roglans^*, Rosa M. Sánchez^*, Manuel Vázquez-Carrera^*, Juan C. Laguna^*, Juan Pedro-Botet and Marta Alegret^*,1

^* Pharmacology Department, Faculty of Pharmacy and Biomedicine Institute (IBUB), University of Barcelona, and Ciber Diabetes y Enfermedades Metabólicas asociadas (CIBERDEM), Instituto de Salud Carlos III, Spain and Department of Medicine, Hospital del Mar, Universidad Autónoma de Barcelona, Spain

To whom requests for reprints should be addressed at ¹ Diagonal 643, Barcelona 08028, Spain. E-mail: alegret{at}ub.edu

Ritonavir, a protease inhibitor used in combination antiretroviral therapy for HIV-1 infection, is associated with an increased risk of premature atherosclerosis. The aim of the present study was to assess the effects of ritonavir, in the absence of added lipoproteins, on the expression of genes that control cholesterol trafficking in human monocytes/macrophages. Design: THP-1 cells were used to study the effects of ritonavir on the expression of CD36, ATP binding cassette transporters A1 (ABCA1) and G1 (ABCG1), scavenger receptor B class I (SR-BI), caveolin-1 and sterol 27-hydroxylase (CYP27). Exposure to ritonavir (2.5 µg/ml) increased CD36 protein (28%, P < 0.05) and mRNA (38%, P < 0.05) in differentiated THP-1 macrophages, but not in undifferentiated monocytes. This effect was not related to the increase in PPAR expression (51%, P < 0.05) caused by ritonavir. Ritonavir also reduced SR-BI protein levels (46%, P < 0.05) and increased CYP27 (43%, P < 0.05) and ABCA1 (49%, P < 0.05) mRNA expression. Liver X receptor (LXR) mRNA, protein and binding activity were also increased by ritonavir treatment. Conclusions: We propose that ritonavir induces ABCA1 expression in THP-1 macrophages through LXR. The increase in ABCA1 and other cholesterol efflux mediators, such as CYP27, may compensate CD36 induction. Therefore, we suggest that the net effect of ritonavir on macrophages in the absence of lipoproteins is not clearly proatherogenic.

Key Words: ritonavir • macrophage • CD36 • ABCA1 • sterol 27-hydroxylase