Objective: Abacavir and didanosine are nucleoside reverse transcriptase inhibitors (NRTI) widely used in therapy for HIV-infection but which have been linked to cardiovascular complications. The objective of this study was to analyze the effects of clinically relevant doses of abacavir and didanosine on human leukocyte–endothelium interactions and to compare them with those of other NRTIs.
Design and methods: The interactions between human leukocytes – specifically peripheral blood polymorphonuclear (PMN) or mononuclear (PBMC) cells – and human umbilical vein endothelial cells were evaluated in a flow chamber system that reproduces conditions in vivo. The expression of adhesion molecules was analyzed by flow cytometry.
Results: Abacavir induced a dose-dependent increase in PMN and PBMC rolling and adhesion. This was reproduced by didanosine but not by lamivudine or zidovudine. Both abacavir and didanosine increased Mac-1 expression in neutrophils and monocytes, but produced no effects on either lymphocytes or the expression of endothelial adhesion molecules. The PMN/PBMC rolling and adhesion induced by abacavir or didanosine did not occur when antibodies against Mac-1 or its ligand ICAM-1 were blocked.
Conclusion: Abacavir induces significant human leukocyte accumulation through the activation of Mac-1, which in turn interacts with its endothelial ligand ICAM-1. The fact that didanosine exhibits similar effects and that lamivudine and zidovudine do not points to a relationship between the chemical structure of NRTIs and the induction of leukocyte/endothelial cell interactions. This mechanism may be especially relevant to the progression of the vascular damage associated with atherosclerosis and myocardial infarction in abacavir and didanosine-treated patients.
aDepartamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Spain
bFundación Hospital Universitario Dr Peset, Spain
cCentro de Transfusiones de la Comunidad Valenciana, Valencia, Spain.
Received 27 December, 2009
Revised 12 March, 2010
Accepted 23 March, 2010
Correspondence to Juan V. Esplugues, Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia. Avda. Blasco Ibáñez 15-17, 46010 Valencia, Spain Tel: +34 96 3864624; fax: +34 96 3983879; e-mail: Juan.V.Esplugues@uv.es