HIV-1 Infection In Fetal/ Pediatric AIDS Brain Tissue

Neurological Disorders And Stroke

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Abstract

HIV-1 associated encephalopathy can show either minor or severe cognitive impariments refered to as the AIDS dementia complex as well as motor dysfunction. HIV-1 causes damage in the human brain through both direct infection and indirect mechanisms through viral structural or non-structural proteins. The ability of HIV-1 proteins, particularly tat, which is a transactivating protein to regulate cellular functions helps explain the dysfunction of the nervous system in brain tissue where there is little evidence of active virus multiplication. We found that HIV-1 infection in glial cells up regulates the synthesis and release of the beta-chemokine MCP-1 which is also found in elevated levels in the CSF of AIDS patients with dementia. Elevated levels of MCP-1 in the CSF is being studied by other AIDS Neuro Centers and has been confirmed by several other laboratories. It may serve as a surrogate marker for AIDS assoicated dementia. We have also shown that human astrocytes are responsible for MCP-1 release and that transcriptional control may be the key factor. The MCP-1 released chemoattracts monocytes across the barrier and upregulates the beta-chemokine HIV-1 co-receptor, CCR5, on migrating monocytes. The promoter sequences of the human MCP- 1 promoter shows inducible NF-1/AP-1 sites which are sensitive to the HIV-1 protein tat. We have identified the distal region of the human MCP-1 promoter as most active in regulating MCP-1 synthesis in astrocytes, indicating a role for DNA binding proteins in astrocytes that are responsive to cytokines like TNF-alpha. We have also found that MCP-1 synthesis is greatly enhanced when human fetal progenitor cells are differentiated to glial phenotypes due to activation of NF-kB in the distal region of the MCP-1 promoter. We are also investigating whether there is direct infection of multipotential progenitor cells and have identified HIV-1 infected cells in pediatric brain tissue in anatomical regions that are the primary site for stem cell migration. Using laser capture microdissection, we have begun to examine well characterized pathological tissue and identified nestin positive cells in the subventricular zone and hippocampus. There are nestin postive, HIV-1 postive cells present in these regions indicating that virus can infect these cell types and perhaps limit their role in neuroregeneration.