Whelan Kathryn T, Lin Chen-Lung, Cella Marina, McMichael Andrew J, Austyn Jonathan M, Rowland-Jones Sarah L
Human Immunology Unit, Nuffield Department of Medicine, University of Oxford, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, GB.
Eur J Immunol. 2003 Sep;33(9):2520-30. doi: 10.1002/eji.200323646.
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.
茚地那韦（IDV）是一种蛋白酶抑制剂，作为抗逆转录病毒疗法的一部分，它能成功抑制HIV-1复制。有证据表明，IDV也可能对宿主蛋白酶产生非特异性作用。在本研究中，我们调查了IDV是否能调节参与树突状细胞（DC）迁移的蛋白酶依赖性分子，而DC迁移是免疫调节中的一个关键过程。将人单核细胞衍生的DC暴露于IDV（IDV-DC），并测定其对炎性趋化因子的跨内皮迁移（TEM）。与未处理的DC相比，IDV-DC的TEM显著受损（p<0.01）。表型分析显示，IDV-DC的DC-SIGN表达降低，这与对固定化ICAM-2的粘附减少相关。然而，暴露于IDV后迁移的减少不能完全归因于单独的DC-SIGN相互作用。对IDV-DC与潜在基质蛋白纤连蛋白相互作用的研究表明，IDV显著损害DC与固定化纤连蛋白的结合（p<0.01）。IDV似乎作用于VLA-4和VLA-5，因为添加拮抗剂单克隆抗体（mAb）同样降低了未处理DC与纤连蛋白的粘附。使用抗VLA-4、VLA-5和抗DC-SIGN mAb联合阻断DC，其对TEM的抑制程度与IDV相似。我们的结果强烈表明，IDV抑制DC迁移所需的宿主蛋白酶，因此可能影响HIV-1感染患者的DC免疫调节。
