The HIV protease inhibitor Indinavir reduces immature dendritic cell transendothelial migration

Kathryn T. Whelan, Chen Lung Lin, Marina Cella, Andrew J. McMichael, Jonathan M. Austyn, Sarah L. Rowland-Jones

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2520-2530
Number of pages11
JournalEuropean Journal of Immunology
Volume33
Issue number9
DOIs
StatePublished - Sep 1 2003

Keywords

  • Adhesion molecules
  • Cell trafficking
  • Dendritic cells
  • HIV
  • Indinavir

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