The HIV protease inhibitor Indinavir reduces immature dendritic cell transendothelial migration

AbstractIndinavir (IDV) is a protease inhibitor that successfully suppresses HIV‐1 replication as part of anti‐retroviral therapy. There is evidence to suggest that IDV may also act non‐specifically upon host proteases. In this study we investigated whether IDV could modulate protease‐dependent molecules involved in dendritic cell (DC) migration — a pivotal process in immunoregulation. Human monocyte‐derived DC were exposed to IDV (IDV‐DC) and transendothelial migration (TEM) to inflammatory chemokines was determined. TEM of IDV‐DC was significantly impaired compared to non‐treated DC (p<0.01). Phenotypic analysis revealed that IDV‐DC had reduced DC‐SIGN expression, correlating with reduced adhesion to immobilized ICAM‐2. Nevertheless, the reduction in migration following exposure to IDV could not be fully attributable to DC‐SIGN interactions alone. Investigation of IDV‐DC interactions with the underlying matrix protein, fibronectin, demonstrated that IDV significantly impaired DC binding to immobilized fibronectin (p<0.01). IDV appeared to act upon VLA‐4 and VLA‐5 since addition of antagonist monoclonal antibodies (mAb) similarly reduced adhesion ofnon‐treated DC to fibronectin. Combined blockade of DC using anti‐VLA‐4, VLA‐5 and anti‐DC‐SIGN mAb inhibited TEM to a similar extent as IDV. Our results strongly suggest that IDV inhibits host proteases necessary for DC migration and may, therefore, affect DC immunoregulation in HIV‐1‐infected patients.