Differential effects of antiretroviral HIV integrase inhibitors on vascular cell adhesion molecules

Integrase strand transfer inhibitors (INSTIs) have been linked to early cardiovascular (CV) complications. Despite the underlying mechanisms remain unclear, a proinflammatory effect has been suggested. Given the role of adhesion molecules in mediating endothelial interactions with leukocytes and platelets during vascular inflammation and thrombosis, we compared the impact of four INSTIs-dolutegravir (DTG), bictegravir (BIC), raltegravir (RAL), and cabotegravir (CAB)-and the non-nucleoside reverse transcriptase inhibitor doravirine (DOR), which is not associated with excessive CV risk, on adhesion molecule expression. Human blood, platelet-rich plasma, and endothelial cells from umbilical veins of healthy donors were incubated with clinically relevant drug concentrations and the expression of leukocyte, endothelium and platelet adhesion molecules was assessed by flow cytometry. BIC and CAB selectively activated neutrophils and monocytes, as evidenced by increased Mac-1 expression and L-selectin shedding. DTG, BIC, and DOR enhanced ICAM-1 expression on endothelial cells, while DTG and BIC also up-regulated VCAM-1, P-selectin and E-selectin levels. Additionally, DTG and BIC potentiated ADP-induced P-selectin expression in platelets. Overall, BIC produced the most significant pro-inflammatory changes, activating leukocytes, endothelial cells, and platelets; DTG primarily targeted the endothelium and platelets; CAB and DOR specifically activated leukocytes and endothelium, respectively, and RAL had no detectable effect. Our findings reveal distinct immunomodulatory profiles among the different INSTIs in vitro, rather than a class-wide effect. Future studies in patients with HIV will be needed to confirm the proinflammatory effects of DTG, BIC and CAB and to explore their potential implications for CV risk.