A significant number of AIDS patients develop a progressive CNS disorder with motor and cognitive deficits called AIDS dementia complex (ADC). ADC has been linked to increasing CNS viral burden, but how HIV mediates central nervous system (CNS) damage is not known. Our central hypothesis is that increasing CNS viral burden is the primary cause of ADC. Disruption of either the physical blood brain barrier or its physiological functions may play a direct role in the progression of CNS damage. As the BBB plays a pivotal role in the entry of HIV into the CNS, it is a logical target for measures designed to prevent ADC. We propose to examine the role of the BBB in ADC by using human autopsy material and two different in vivo models. We have available a bank of frozen and fixed CNS autopsy tissues from approximately 500 AIDS patients with premortem neurologic symptoms ranging from asymptomatic to severe dementia. The in vivo models will allow us to examine the temporal sequence of BBB abnormalities and to assess the efficacy of treatment strategies. The first model uses human fetal CNS aggregates grafted into the brain of SCID mice, and the second uses ts-1, a neurotropic murine leukemia virus (MuLV), as a model of chronic retroviral encephalitis. In SA#1 we will define the temporal sequence of morphologic and functional changes of the BBB. Ultrastructural studies will examine morphologic abnormalities, and immunocytochemistry with laser confocal microscopy will assess the status of endothelial transport proteins. Ingress of macrophages into the CNS may be the key development in the onset of ADC and is probably regulated by adhesion molecules on the BBB. SA#2 will characterize the presence and distribution of adhesion molecules on the BBB. Little is known about adhesion molecules necessary for the trafficking of monocytes/ macrophages into the CNS in retroviral infected brains. SA#3 will examine immune cell trafficking into the CNS. Using our SCID model the kinetics of CNS penetration by HIV-infected and non-infected T-cells and monocytes will be studied. Finally, the prevention of ADC is the ultimate aim in all of these studies. SA#4 will examine the effect of therapeutic intervention on the BBB and the onset of retroviral encephalitis. We believe that by using these two very different models and by direct integration of findings with AIDS autopsy material, we are in a unique position to delineate important characteristics of the BBB in ADC and the potential for therapeutic intervention.
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