The HIV protease inhibitor indinavir reduces immature dendritic cell transendothelial migration.
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 in...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
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2003
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| _version_ | 1797074540823576576 |
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| author | Whelan, K Lin, C Cella, M Mcmichael, A Austyn, J Rowland-Jones, S |
| author_facet | Whelan, K Lin, C Cella, M Mcmichael, A Austyn, J Rowland-Jones, S |
| author_sort | Whelan, K |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T23:37:41Z |
| format | Journal article |
| id | oxford-uuid:6e372f44-1185-4d49-bf8a-a16a26b42a81 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:37:41Z |
| publishDate | 2003 |
| record_format | dspace |
| spelling | oxford-uuid:6e372f44-1185-4d49-bf8a-a16a26b42a812022-03-26T19:23:00ZThe HIV protease inhibitor indinavir reduces immature dendritic cell transendothelial migration.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6e372f44-1185-4d49-bf8a-a16a26b42a81EnglishSymplectic Elements at Oxford2003Whelan, KLin, CCella, MMcmichael, AAustyn, JRowland-Jones, SIndinavir (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. |
| spellingShingle | Whelan, K Lin, C Cella, M Mcmichael, A Austyn, J Rowland-Jones, S The HIV protease inhibitor indinavir reduces immature dendritic cell transendothelial migration. |
| title | The HIV protease inhibitor indinavir reduces immature dendritic cell transendothelial migration. |
| title_full | The HIV protease inhibitor indinavir reduces immature dendritic cell transendothelial migration. |
| title_fullStr | The HIV protease inhibitor indinavir reduces immature dendritic cell transendothelial migration. |
| title_full_unstemmed | The HIV protease inhibitor indinavir reduces immature dendritic cell transendothelial migration. |
| title_short | The HIV protease inhibitor indinavir reduces immature dendritic cell transendothelial migration. |
| title_sort | hiv protease inhibitor indinavir reduces immature dendritic cell transendothelial migration |
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