EXTENSION OF MERIT AWARD 1 R37 MH 46815-04

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The hypothesis to be tested in this proposal is that different human immunodeficiency virus-1 (HIV-1) isolates vary in their neural system (CNS) organotypic tissue culture model. Additionally, because these variations may be reflected in vivo by the spectrum of neuropathologic changes associated with acquired immunodeficiency syndrome (AIDS), experiments will be conducted to explore the correlation between in vitro and in vivo pathologic changes. Neurologic dysfunction is a common, sometimes initial and diagnostic, finding in AIDS. In adult AIDS, the relationship between HIV-1 nd neuropathology remains unclear but, however, in pediatric AIDS this proposed direct relationship between virus and pathology is less controversial. The evidence to support a causal relationship between HIV-1 and the neuropathology of pediatric AIDS stems from clinical observations of children born with congenital HIV-1 infection and pathologic studies which surveyed pediatric and human fetal brains using immunocytochemical and nucleic acid techniques in combination with light and electron microscopy. Because these neural environments are more pristine than adult brains of AIDS patients, a more directly related association between HIV-1 and nervous system pathology emerged. In pediatric brain and spinal cord an array of changes were observed which ranges from subacute encephalitic to CNS vasculopathy to axon and myelinopathy. A similarly diverse picture is emerging in studies, in our laboratories, on HIV-1 related neuropathology in fetal brain. Because recently, opinion has developed that HIV-1 may exhibit different cellular tropisms, the most common of which are the lymphocytotrophicc (L) and monocytotrophic (M) isolates; this study was conceived so as to explore this question using a recently developed tissue culture model of human fetal CNS tissue maintained in organotypic culture. Cells in this culture system develop and differentiate into neurons forming synapses, astrocytes, oligodendtocytes, microglia and vascular endothelia which express cell-type specific markers. Preliminary studies have shown that the IIIb and RF2 laboratory isolates of HIV-1 can induce morphologic changes in well- differentiated cultures similar to changes observed in vivo. Therefore, this proposal will further explore and define the ability of HIV-1 to either directly or indirectly cause CNS pathology. Such insights may permit the design of improved preventative or therapeutic protocols for combatting HIV infection.