HIV-1 Tat Protein Stimulates In Vivo Vascular Permeability and Lymphomononuclear Cell Recruitment

Abstract

HIV-1 Tat protein released by infected cells is a chemotactic molecule for leukocytes and induces a proinflammatory program in endothelial cells (EC) by activating vascular endothelial growth factor (VEGF) receptors expressed on both cell types. Its potential role in causing vascular permeability and leukocyte recruitment was studied in vivo following its s.c. injection in mice. Tat caused a dose-dependent early (15 min) and late (6 h) wave of permeability that were inhibited by a neutralizing Ab anti-VEGF receptor type 2. Tissue infiltration of lymphomononuclear cells, mainly monocytes (76%), was evident at 6 h and persisted up to 24 h. WEB2170, a platelet activating factor (PAF) receptor antagonist, reduced the early leakage by 70–80%, but only slightly inhibited the late wave and cell recruitment. In vitro, Tat induced a dose-dependent flux of albumin through the EC monolayer that was inhibited by Ab anti-vascular VEGF receptor type 2 and WEB2170, and PAF synthesis in EC that was blocked by the Ab anti-VEGF receptor type 2. Lastly, an anti-monocyte chemotactic peptide-1 (MCP-1) Ab significantly reduced the lymphomononuclear infiltration elicited by Tat. In vitro, Tat induced a dose-dependent production of MCP-1 by EC after a 24-h stimulation. These results highlighted the role of PAF and MCP-1 as secondary mediators in the onset of lymphomononuclear cell recruitment in tissues triggered by Tat.

Interactions between endothelial cells and HIV-1

“…The natural ligands of VEGFR2 belong to the VEGF family [92] and a neutralizing antibody anti-VEGFR2 or cross-desensitization between Tat and VEGF-A 165 block the activation of the receptor as well as the migration of EC triggered by Tat. These results are also supported by recent data showing that Tat has vasopermeabilizing effect by a direct action on EC [93,94], as demonstrated earlier for VEGF-A [92]. These effects are blocked by functional inactivation of VEGFR-2 [93].…”

“…These results are also supported by recent data showing that Tat has vasopermeabilizing effect by a direct action on EC [93,94], as demonstrated earlier for VEGF-A [92]. These effects are blocked by functional inactivation of VEGFR-2 [93].…”

“…As mentioned before, Tat induces the expression of E-selectin, up-regulates ICAM-1 and VCAM-1 in macrovascular and microvascular EC [69,70,112,113] and supports leukocyte adhesion. Furthermore, it stimulates transcription and release of IL-8 [112] and MCP-1 [93] that are powerful leukocytes chemoattractants. In vivo, the effect of Tat on leukocyte recruitment is preceded by an increased in vascular permeability, which is caused by the synthesis of platelet-activating factor in EC and may facilitate cell transmigration [93].…”

“…Furthermore, it stimulates transcription and release of IL-8 [112] and MCP-1 [93] that are powerful leukocytes chemoattractants. In vivo, the effect of Tat on leukocyte recruitment is preceded by an increased in vascular permeability, which is caused by the synthesis of platelet-activating factor in EC and may facilitate cell transmigration [93].…”

HIV-1 Tat-Mediated Apoptosis in Human Brain Microvascular Endothelial Cells

“…In addition, HIV-1 Tat protein induced the production of IL-8 by human brain-derived EC (33,46), and increased endothelial permeability through tyrosine kinase-and mitogen-activated protein kinase-dependent pathways (34,47).…”