Blood-brain barrier disruption in simian immunodeficiency virus encephalitis.

Infected monocyte-derived macrophages (MDM) are thought by some investigators to play a central role in the neuropathogenesis of human immunodeficiency virus encephalitis (HIVE). It was recently proposed that these cells gain access to the central nervous system (CNS) through disruptions in blood-brain barrier (BBB) tight junctions, which occur in HIVE in association with accumulation of activated, HIV-1-infected, perivascular macrophages and serum protein extravasation (Am J Pathol 1999, 155: 1915-27). The present study tested this hypothesis in basal ganglia tissue from simian immunodeficiency virus (SIV)-infected macaques with encephalitis by examining vessels for immunohistochemical alterations in the tight junction-associated proteins, occludin and zonula occludens-1 (ZO-1). Compared to non-infected macaques and SIV-infected macaques without encephalitis, cerebral vessels from macaques with SIVE showed fragmentation and decreased immunoreactivity for both tight junction proteins. These alterations were associated with accumulation of perivascular macrophages and aberrant occludin and ZO-1 immunoreactivity within these cells. In addition, perivascular extravasation of fibrinogen, a plasma protein, and a change from a strong linear staining pattern to a more irregular pattern of glucose transporter isoform-1 (GLUT-1), a metabolic BBB marker, were observed in regions with vascular tight junction protein alterations. These findings demonstrate that tight junction disruption occurs in SIVE in association with perivascular macrophage accumulation. While it cannot be ascertained from these studies whether such changes precede macrophage infiltration, or are secondary to the chronic presence of macrophages around cerebral vessels, disruptions in BBB integrity could serve as portals for additional accumulation of perivascular macrophages in SIVE.

Differential expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in chronic murine retroviral encephalitis.

The cell adhesion molecules, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1, are important mediators of immune interactions within the central nervous system (CNS). A wide variety of pro-inflammatory insults to the brain, including viral infection, result in upregulation of these molecules on brain endothelial cells, astrocytes, and microglia. This study investigated the expression of ICAM-1 and VCAM-1 in chronic encephalitis induced by infection with a temperature sensitive (ts-1) strain of Moloney murine leukaemia virus (MoMuLV), an ecotropic murine retrovirus. During the late stages of disease, viral antigen was present in both endothelial cells and microglia, but not astrocytes, in regions of spongiform change and gliosis. In these areas, ICAM-1 staining was detected on activated microglia, but not on endothelial cells or astrocytes. In contrast, no cells showed increased VCAM-1 expression in the CNS. These findings demonstrate that there is cell-specific, differential expression of these adhesion molecules in ts-1 retroviral encephalitis. The lack of endothelial cell expression correlates with the characteristic lack of lymphocytic infiltrate in this chronic retroviral encephalitis and suggests that increased microglial ICAM-1 expression may play a role in the pathogenesis of MoMuLV (ts-1)-mediated neurodegeneration.

Blood-brain barrier tight junction disruption in human immunodeficiency virus-1 encephalitis.

The blood-brain barrier (BBB) plays a critical role in regulating cell trafficking through the central nervous system (CNS) due to several unique anatomical features, including the presence of interendothelial tight junctions that form impermeable seals between the cells. Previous studies have demonstrated BBB perturbations during human immunodeficiency virus encephalitis (HIVE); however, the basis of these permeability changes and its relationship to infiltration of human immunodeficiency virus type 1 (HIV-1)-infected monocytes, a critical event in the pathogenesis of the disease, remains unclear. In this study, we examined CNS tissue from HIV-1-seronegative patients and HIV-1-infected patients, both with and without encephalitis, for alterations in BBB integrity via immunohistochemical analysis of the tight junction membrane proteins, occludin and zonula occludens-1 (ZO-1). Significant tight junction disruption (P < 0.001), as demonstrated by fragmentation or absence of immunoreactivity for occludin and ZO-1, was observed within vessels from subcortical white matter, basal ganglia, and, to a lesser extent, cortical gray matter in patients who died with HIVE. These alterations were also associated with accumulation of activated, HIV-1-infected brain macrophages, fibrinogen leakage, and marked astrocytosis. In contrast, no significant changes (P > 0.05) were observed in cerebellar tissue from patients with HIVE compared to HIV-seronegative patients or HIV-1-infected patients without encephalitis. Our findings demonstrate that tight junction disruption is a key feature of HIVE that occurs in regions of histopathological alterations in association with perivascular accumulation of activated HIV-1-infected macrophages, serum protein extravasation, and marked astrocytosis. We propose that disruption of this key BBB structure serves as the main route of HIV-1-infected monocyte entry into the CNS.