Abacavir induces an increase in leukocyte-endothelium crosstalk in blood from HIV-infected patients

Aim: Abacavir (ABC) has been associated with myocardial infarction risk. We have demonstrated in vitro (in cells from healthy donors) that clinical concentrations of ABC, but not of tenofovir (TFV), exert actions that are both proinflammatory (by inducing leukocyte-endothelium interactions) and prothrombotic (by promoting the interaction of platelets with other important vascular cells such as the endothelium or neutrophils, and also by promoting thrombus formation). The aim of this study was to give physiological relevance to these data by analysing the effects of ABC on leukocyte-endothelium interactions in cells isolated from the blood of HIV-infected patients treated with TFV. Methods: We used blood drawn from HIV-infected patients at Hospital Clínico Universitario de Valencia who had been receiving an antiretroviral therapy regime that included TFV (either tenofovir alafenamide or tenofovir disoproxil fumarate) for at least 6 months. Polymorphonuclear (PMNs) cells were isolated using a method based on density gradient and were then treated with clinically relevant concentrations of ABC (5 µg/ml, 4 h) or vehicle. After this period, the interactions of PMNs with a non-infected endothelium monolayer (rolling, rolling velocity and adhesion) were evaluated using a parallel-plate flow chamber system. By means of flow cytometry we also assessed the expression of different leukocyte adhesion molecules involved in leukocyte-endothelium interactions, such as LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18), gp150,45 (CD11c/CD18) and L-selectin (CD62L). Results: A total of 28 patients were included in the study: age was 47.04 ±2.62 years, 92.86% were males, and CD4+ T-cell count was 774.2 ±82.24 cells/mm3. PMN rolling velocity was reduced, while rolling along and adhesion to the endothelium were significantly higher in the ABC-treated group than in the vehicle-treated group (Figure 1A–C). Moreover, ABC induced a rise in the expression of neutrophil CD11b, CD11c and CD18 (Figure 1D–F). The other leukocyte adhesion molecules analysed (i.e., CD11a and CD62L) were not modified by ABC. Conclusions: ABC enhances PMN-endothelium interactions, thus promoting the initial phases of the inflammatory process. Furthermore, it induces the expression of leukocyte adhesion molecules Mac-1 and gp 150,45 which may be involved in the aforementioned interactions. Our results give support to an increased risk of myocardial infarction in ABC-treated HIV patients.