The overall hypothesis to be tested in this proposal is that exposure of the human fetal central nervous system (CNS) to HIV-1 may be sufficient to cause the neurological dysfunction characteristic of pediatric AIDS. The basis for this assumption is that a significant number of children with AIDS and others without clinical signs of disease but with congenital HIV-1 infection exhibit cognitive, behavioral, and neurodevelopmental abnormalities. Significant neuropathologic changes in the CNS of children and fetuses infected by HIV-1 but without other signs of AIDS have also been noted. Furthermore, HIV-1 nucleic acid sequences or proteins and signs of productive viral infection have been observed in the affected tissues and studies in vitro have demonstrated HIV-1 infection of glial cells. To define the role of HIV-1 in pediatric AIDS more precisely, a group of neuroscientists, each expert in a different neural cell type, has come together to pursue this question using a combination of morphologic, biochemical an molecular biologic techniques. Because of alterations in normal cognitive development in HIV-1 infected children, Project 1 will study the effect of HIV-1 on neuronal differentiation with a focus on specific neurotransmitter systems and on neuronal cytoskeletal components. Project 2 will complement Project 1 in that it will focus primarily on the astrocyte cytoskeleton and metabolic function in HIV-1 infection because of the reactive astrocytosis described in pediatric AIDS and the ability of astrocytes to elicit cytokines which may modulate CNS function. Project 3 will focus on microglia in the fetal CNS because this cell type is believed to be pivotal in AIDS neuropathology. This project will examine HIV-1 infection of microglia in vivo and in vitro and examine the role of cytokines in tissue damage. Because myelin pathology is prominent in pediatric AIDS, Project 4 will examine myelinogenesis and dysmyelination in the human fetal CNS exposed to HIV-1 in vivo. Project will also investigate the mechanisms related to myelin biology using dissociated cell culture and organotypic explant cultures. Project 5 focuses on the involvement of endothelial cells in the pathophysiology of CNS disease because evidence indicates that endothelial cells may be infected by HIV-1 and they provide the first barrier to viral entry into the CNS. Additionally, endothelial cells produce cytokines which may be involved in the pathophysiology of AIDS. Lastly, Project 6 will use an in vitro neuronal cell model to explore the interaction of HIV-1 genes on host cell gene expression and converse, host cell control over HIV-1 gene expression. The studies proposed in this Program Project application should answer many of the pressing questions related to nervous system disease in pediatric AIDS. Among these questions are the determination of a direct neurotropism of HIV-1; factors that are involved in the neuroinvasiveness of this virus; and, mechanisms of HIV neurovirulence. These studies may suggest new strategies to prevent or treat more effectively neurologic disease in pediatric AIDS.
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