Efectos proinflamatorios de los fármacos antirretrovirales inhibidores de la transcriptasa inversa análogos de nucleósido in vitro e in vivo

Nucleoside reverse transcriptase inhibitors (NRTI) are a family of drugs used in the treatment of the Human Immunodeficiency Virus (HIV) infection. This antiretroviral group is a constant in all therapeutic options in combination with drugs from other antiretroviral families. The administration of these compounds, especially abacavir (ABC) and didanosine (ddI), has been linked with cardiovascular side effects, though the mechanism implicated remains unclear. Using in vitro and in vivo models, we evaluated the effects of clinically relevant concentrations of these antiretroviral drugs on leukocyte-endothelium interactions, which are the first phase in the onset of cardiovascular diseases with an inflammatory component, such as myocardial infarction, atherosclerosis and thrombosis. ABC (the most employed drug of this family and a purine analogue), induced leukocyte-endothelium (venular and arteriolar) interactions in vitro and in vivo, and enhanced the expression of the leukocyte adhesion molecule Mac-1 (CD11b/CD18) on neutrophils and monocytes from both human and rat blood. Although ICAM-1 expression was not modified by ABC, the leukocyte accumulation it induced was mediated by Mac-1/ ICAM-1 interaction; this was evident in the fact that blocking antibodies against these adhesion molecules prevented the different leukocyte parameters. Further studies in which each cellular type (endothelium or leukocyte) was treated individually revealed that the endothelium also played a key role in this response. Moreover, at the endothelial level, ABC was found to promote reactive oxygen species (ROS) production, as well as traslocation of NF-κB to the nucleus and cytosolic degradation of its inhibitor IκB-α. Our studies have highlighted a structure-activity relationship in the way the different antiretroviral drugs work: didanosine (ddI, purine analogue) reproduced the toxic effects of ABC, while the pyrimidine analogues lamivudine (3TC), zidovudine (ZDV) and emtricitabine (FTC) or the nucleotide analogue tenofovir (TDF) did not produce significant changes in either of the parameters evaluated. This suggests that ABC and ddI exert an effect on the purine signalling pathway, and that the ATP molecule is implicated in these effects. In this way, ABC increases intracellular levels of ATP and undermines the expression of CD73 (an enzyme responsible for the degradation of ATP) on the endothelium and on leukocytes. Furthermore, it has been observed that the role of ATP in the leukocyte recruitment induced by this NRTI takes place through its P2X7 receptors. Finally, the therapeutic combination of ABC/3TC produced the same proinflammatory effect than ABC. However, the alternative combination of FTC/TDF did not promote this action. In conclusion, the present study highlights the proinflammatory mechanism by which the purine analogues NRTI, and specifically ABC, induce leukocyte accumulation which precedes the development of cardiovascular diseases. It also highlights the relevance of the chemical structure of these drugs in the genesis of this toxic effect and supports a clinical association between these drugs and cardiovascular pathologies.