This investigator-initiated interactive research project is designed to combine in vitro and in vivo studies to examine the role of the blood- brain barrier in central nervous system disease induced by HIV. The integrity of the blood-brain barrier is essential for normal brain function. However abnormalities in this barrier have been reported in AIDS patients, and has been found at a high frequency in those with HIV-induced dementia. Such a defect may play a role in causing the CNS functional deficits seen in AIDS by a number of mechanisms, including facilitating a high level of infection of the brain by virus or infiltration by virus- carrying cells, attracting inflammatory cells to the brain which themselves can have toxic effects, and/or disturbing the normal homeostasis of the brain by allowing damaging molecules to enter the CNS that are normally excluded. Determining the role of the blood-brain barrier in HIV-induced neuropathogenesis and the etiopathogenesis of such disorders is extremely limited in human disease due to the impossibility of controlling important scientific variables such as viral strains, timing of infection, and the restricted access to CNS-derived samples. The rhesus monkey-SIV model is ideal in this respect, as many of the CNS disease parameters in this model mimic those in humans HIV. In this study, we will first examine the role of blood-brain barrier dysfunction by comparing breakdown of the barrier to virologic, immunologic, pathologic, and functional parameters measured in animals infected with a neurovirulent strain of SIV. Second, we will study the relationship of tropism of the virus to infect the brain capillary endothelial cells, the central components of the blood-brain barrier, with neurovirulence. Possible etiopathogenic mechanisms in CNS infection blood-brain barrier dysfunction induced by this infection will be examined. Finally, a brain capillary endothelial cell-tropic molecular clone of SIV will be derived and studied for its neuropathogenic effects. These studies will allow the further development of an animal model to study the effect of HIV on the CNS, and yield insights into the role of the blood-brain barrier in disease, the mechanisms of CNS infection and dysfunction, and its prevention and treatment.
