HIV-1 infection of the CNS has devastating consequences, with approximately 30% of infected patients, particularly children, developing HIV-1 encephalitis (HIVE) and/or dementia. HIV-1 enters the brain early after infection. Despite HAART, inflammation persists in the CNS, and microglia may serve as reservoirs ofHIV-1. The neuropathology of HIV-1 infection includes demyelination, reactive astrocytes, multinucleated giant cells, accumulation of macrophages, and neuronal injury and loss. There is also abnormal BBB permeability. These pathologies are due to the presence of virus as well as indirect effects of HIV-1 infection, including the elaboration of tat, gpl20, cytokines and chemokines that mediate alterations seen in CNS cells including apoptotic cell death. HIV-1 may be disseminated into the CNS by migration of infected monocytes across the BBB, a process mediated, in part, by chemokines. While chemokines play an essential role in inflammation-mediated sequelae in HIVE and dementia there may be other functions that they mediate in these pathologies. We demonstrated that MCP- 1 protects neurons and astrocytes from tat or NMDA induced apoptosis. We hypothesize that chemokines play several roles in HIVE and dementia. They recruit subsets of mononuclear cells into the CNS. They cause microglia to migrate to sites of infection and inflammation, resulting in microglia fusion with and infection by HIV-infected monocytes. These HIV-infected or activated cells elaborate cytokines and viral proteins that will alter the structure and permeability of the BBB as well as gene expression of microglia, astrocytes and neurons. Chemokines act upon CNS ceils to induce additional chemokine expression, amplifying inflammation. We also have data that chemokines are neuroprotective, limiting the neurotoxicity of HIV-1 secreted proteins. To test this hypothesis, we propose to: 1.Characterize the transmigration of HIV-infected monocytes across our model of the BBB in response to MCP-1. The mechanisms by which MCP-1-mediated transmigration of HIV-infected monocytes alter tight junction protein and MMP expression by and permeability of cocultured EC and astrocytes will be examined. 2. Study chemokine-induced MCP-1 and chemokine receptor expression in astrocytes. 3. Determine the signaling pathways involved in tat and CD40 ligand (CD40L)- induced MCP- 1 expression by microglia. We included CD40L because we showed that CD40 expression is increased on microglia in CNS AIDS, and that CD40L, on infiltrating leukocytes, induces chemokine expression by 111icroglia. The functional consequences of MCP-1 production will be assessed. 4. Characterize the mechanisms that mediate tat-induced apoptosis in neurons and by which MCP-1 protects cells from apoptosis. ? ?
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