HIV-1 Envelope Glycoprotein 120 Increases Intercellular Adhesion Molecule-1 Expression by Human Endothelial Cells

Abstract

SUMMARY:Human immunodeficiency virus type 1 (HIV-1) infection is often associated with central nervous system damage and vascular complications. However, the mechanisms of this association are largely unknown. We examined the effect of HIV-1 envelope glycoprotein 120 (gp120) on cell adhesion molecule expression by endothelial cells. We found, for the first time, that both soluble and membrane-bound gp120 could significantly increase the expression of human endothelial intercellular adhesion molecule-1 (ICAM-1) at both mRNA and protein levels, but not vascular cell adhesion molecule-1 and E-selectin. The specificity of gp120-mediated response was demonstrated by blocking experiments using a specific monoclonal antibody against gp120, which successfully abolished the gp120-mediated increase of ICAM-1 expression. Furthermore, there was a significant increase of human monocytic cell line THP-1 adherence onto the gp120-treated endothelial monolayers. This increased cell adhesion was effectively blocked by either anti-gp120 or anti-ICAM antibodies. These findings suggest that HIV-1 gp120-mediated endothelial ICAM-1 expression could be one of the important mechanisms of HIV-1 pathogenesis. (Lab Invest 2002, 82:245-255). B oth human immunodeficiency virus (HIV)-positiveand acquired immune deficiency syndrome (AIDS) patients often have significantly increased levels of circulating cell adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) (Greenwood et al, 1998; Seigneur et al, 1997). Serum ICAM-1 levels correlate well with AIDS progression in HIV type 1 (HIV-1)-infected patients (Galea et al, 1997). Endothelial cells and leukocytes from these patients exhibit a significant increase of such adhesion molecules (Pillet et al, 1999;Zietz et al, 1996). HIV-1 particles also incorporate many cell adhesion molecules (Guo and Hildreth, 1995). HIV-associated ICAM-1 is biologically active and can enhance virus infectivity (Fortin et al, 1997) and virus-induced syncytium formation (Gruber et al, 1991). ICAM-1-bearing viruses are less susceptible to neutralization by anti-envelope glycoprotein 120 (gp120) monoclonal antibodies than the same virus produced in cells expressing no ICAM-1 (Sawyer et al, 1994). HIV-1 replication in monocytes/macrophages is significantly enhanced by interaction with endothelial cells through cell adhesion molecules (Gilles et al, 1995). In addition, alterations in expression of cell adhesion molecules by leukocytes and endothelial cells can increase leukocyte migration into the tissues, which may result in certain organ damage. Indeed, HIV-1-infected leukocytes can transmigrate into the central nervous system and cause encephalopathy (Nottet, 1999). Endothelial cell dysfunction and leukocyte infiltration may also be attributable to the increased frequency of vascular complications such as atherosclerosis in HIV-1-infected patients (Constans et al, 1995;Tabib et al, 2000).Several factors may contribute to the increased levels of cell adhesion mole...

Induction of Intercellular Adhesion Molecule-1 on Human Brain Endothelial Cells by HIV-1 gp120: Role of CD4 and Chemokine Coreceptors

“…Gp120-induced expression of ICAM-1 was not caused by contaminating endotoxin in the gp120 preparation because polymyxin B did not inhibit the response. Moreover, antibodies against gp120 blocked gp120-induced responses in ICAM-1 expression (not shown), which is consistent with the results of Ren et al (2002) and our previous findings on gp120-induced monocyte migration (Stins et al, 2001). The gp120-mediated increases in ICAM-1 expression are mediated at the mRNA level, which is in accordance with the findings of Ren et al (2002).…”

“…We were the first to show that gp120 can activate HBMEC from children in up-regulation of VCAM-1, intercellular adhesion molecule (ICAM)-1, and increased monocyte transmigration . Other investigators have also shown the gp120-mediated induction of ICAM-1 on endothelial cells derived from different origins: lung, skin, coronary artery, and umbilical vein (Ren et al, 2002). However, the underlying mechanisms involved in gp120-mediated activation of HBMEC are unclear (eg, roles of CD4, CCR3, CCR5, and CXCR4 receptors or other nonchemokine receptors).…”

State of the Science Conference

“…Endothelial dysfunction is present in ARV-naïve HIV-infected patients, but improves only somewhat with introduction of ARV therapy, potentially due to negative effects of specific individual ARV drugs, virally-protein mediated endothelial activation (35), or chemokine dysregulation, with activation of macrophages, smooth muscle cells and enhanced atheroma formation. Data on direct infection of the vasculature are limited (36).…”

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

“…Endothelial cells have been shown to be variably permissive for HIV infection. The HIV virus itself is able to penetrate coronary artery and brain microvascular endothelial cell membranes and to initiate inflammatory and biochemical intracellular reactions [198,199]. The activation of endothelium induced by either HIV infection itself or by a leukocyte-mediated inflammatory cascade triggered by the same virus leads to an increased expression of endothelial cellular adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1], E-selectin, P-selectin, thrombomodulin, tissue plasminogen activator (tPA), and PAI-1.…”