698 Macaques Inoculated with a Pathogenic Simian-Human Immunodeficiency Virus Develop Disruption of the Blood-brain Barrier Early after Inoculation E. B. Stephens*, E. Pacyniak, N. E. J. Berman, D. K. Singh Univ of Kansas Med Ctr, Kansas City
Background: Previous studies have shown that at the end stage of neuroAIDS in humans and macaques the blood brain barrier (BBB) is disrupted. No studies have examined the integrity of the BBB during acute stages of infection. Simian-human immunodeficiency virus (SHIV) is a chimeric virus with the tat,rev, vpu, and env genes from HIV-1 in the genetic background of pathogenic SIV. It is capable of early neuro-invasion and causes encephalitis in macaques. Previously, we showed that pig-tailed macaques inoculated with pathogenic SHIV50OLNV developed astrocytosis and virus could be detected in the majority of brain regions analyzed.
Methods: In this study, we investigated the integrity of the blood brain barrier (BBB) in 5 pig-tailed macaques inoculated with pathogenic SHIV50OLNV and sacrificed after 2 weeks. Whole brain sections were prepared and integrity of the blood brain barrier was assessed by immunohistochemical staining for fibrinogen. The extravasation of fibrinogen, a high molecular weight plasma protein, in the neural parenchyma was used as the marker for disruption of the BBB.
Results: The results of our immunohistochemical analysis revealed disruption of the BBB in all 5 macaques inoculated with pathogenic SHIV50OLNV. Staining for fibrinogen and albumin was highest around the large blood vessels of the subcortical regions of the brain and least intense in the cortical regions. Expression of zona occludens 1 (ZO-1), a marker of integrity of tight junctions, was found to be decreased in the brains of macaques with BBB disruption. In contrast, uninoculated macaques or macaques inoculated with a non-pathogenic SHIV for over 1 year that developed no significant drop in CD4+ T-cell levels, exhibited no disruption of the BBB.
Conclusions: These results represent the first documentation that the BBB is transiently disrupted during the acute stage of infection by lentiviruses and may partly explain the viral neuro-invasion and astrocytosis that occurs at the early stages of infection.