The HIV protease inhibitor indinavir reduces immature dendritic cell transendothelial migration.

Journal article

Indinavir (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 of non-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.

Authors: Whelan, K; Lin, C; Cella, M; Mcmichael, A; Austyn, J

• Publication status: Published
• Journal: European journal of immunology
• Volume: 33
• Issue: 9
• Pages: 2520-2530
• Publication date: 2003-09-01
• DOI: 10.1002/eji.200323646
• EISSN: 1521-4141
• ISSN: 0014-2980
• Language: English
• Keywords: Cell Movement; Immunoglobulins; Dendritic Cells; HIV Protease Inhibitors; Antigens, CD; Cell Adhesion Molecules; Lectins, C-Type; HIV Infections; Indinavir; Integrin alpha5beta1; HIV-1; Receptors, Cell Surface; Integrin alpha4beta1; Membrane Glycoproteins; Humans; Endothelium