Abacavir and didanosine induce the interaction between human leukocytes and endothelial cells through Mac-1 upregulation.
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.


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.


CONCLUSIONS
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.
De Pablo
Carmen
C
Departamento de Farmacología and CIBERehd, Universidad de Valencia, Spain.
Orden
Samuel
S
Apostolova
Nadezda
N
Blanquer
Amando
A
Esplugues
Juan V
JV
Alvarez
Angeles
A
D000704:Analysis of Variance; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects; D016049:Didanosine / Q000494:pharmacology*; D015224:Dideoxynucleosides / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D000099227:Abacavir
D015815:Cell Adhesion Molecules; D016049:Didanosine; D015224:Dideoxynucleosides; D016177:Macrophage-1 Antigen; D018894:Reverse Transcriptase Inhibitors; D000099227:Abacavir