Blood–brain barrier disruption in simian immunodeficiency virus encephalitis

Abstract

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.

Metabolomic analysis of the cerebrospinal fluid reveals changes in phospholipase expression in the CNS of SIV-infected macaques

“…A compromise of the blood-brain barrier does occur in both SIV (45,46) and HIV infection (47,48), and indeed, we found an increase in albumin in the CSF. It will be interesting to examine the CSF metabolome in other CNS conditions in which the blood-brain barrier is or may be compromised, such as brain trauma (49), Alzheimer and Parkinson diseases (50), multiple sclerosis (51), and other infections that result in encephalitis and/or meningitis.…”

Effect of Efflux Inhibition on Brain Uptake of Itraconazole in Mice Infected withCryptococcus neoformans

“…Several examples of modifications of the BBB by pathogens involved in meningitis have been reported in literature. In AIDS patients suffering from encephalopathy, tight junctions are altered by transport of macrophages infected with HIV-1 through the BBB (Luabeya et al, 2000). In cerebral malaria, Brown et al (1999) reported that adhesion proteins (occludine, vinculine, ZO-1) were altered in cellular junctions and were responsible for a BBB rupture.…”

Blood-brain barrier tight junctions are altered during a 72-h exposure to λ-carrageenan-induced inflammatory pain

“…However, several recent studies (24,29,32,42) have clearly shown that occludin and ZO-1 are important regulatory proteins in maintaining BBB tight junctional integrity during pathological insult.…”