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

The blood-brain barrier (BBB) plays a critical role in regulating cell traf ficking through the central nervous system (CNS) due to several unique anat omical features, including the presence of interendothelial tight junctions that form impermeable seals between the cells. Previous studies have demon strated BBB perturbations during human immunodeficiency virus encephalitis (HIVE); however, the basis of these permeability changes and its relationsh ip to infiltration of human immunodeficiency virus type 1 (HIV-1)-infected monocytes, a critical event in the pathogenesis of the disease, remains unc lear, In this study, we examined CNS tissue from HIV-1-seronegative patient s and HIV-1-infected patients, both with and without encephalitis, for alte rations in BBB integrity via immunohistochemical analysis of the tight junc tion 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 ves sels from subcortical white matter, basal ganglia, and, to a lesser extent, cortical gray matter in patients who died with HIVE. These alterations wer e also associated with accumulation of activated, HIV-1-infected brain macr ophages, fibrinogen leakage, and marked astrocytosis. In contrast, no signi ficant 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 disrupti on is a key feature of HIVE that occurs in regions of histopathological alt erations in association with perivascular accumulation of activated HIV-1-i nfected macrophages, serum protein extravasation, and marked astrocytosis. We propose that disruption of this key BBB structure serves as the main rou te of HIV-1-infected monocyte entry into the CNS.