We have previously shown that the HIV-1 transactivating protein, tat, is able to increase the activity of two cellular proteins. Both the transcription factor, NF-kB and the cellular protein kinase, PKC, demonstrated higher activity when astrocytes were treated with soluble tat. The ability of HIV-1 factors to regulate cellular functions may help explain the dysfunction of the nervous system in the brain tissue with little evidence of active virus multiplication. Also we found that HIV-1 that 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. There was also elevated levels of mRNA to MCP-1 in brain tissue from demented patients. Investigations of CSF samples from HIV-1 infected non-demented patients as well as non neurologically impaired patients did not show increases in MCP-1 in the CSF. Also there was no evidence for other chemokines in the CSF of demented patients suggesting that MCP-1 plays an unique and important role in pathogenesis. The molecular regulation of MCP-1 in astrocytes may be controlled by transcription factors which also regulate JCV infeciton, namely NF-1. 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 also established a cell culture model of HIV-1 infection in human astrocytes closely resembling a viral latency. Upon treatment of HIV-1 latenly infected cells with proinflammatory cytokines like TNF-a, the viral genome is activated and new progeny virions are released. This infectious process however is not cytopathic to the cells which suggests that the astrocyte may serve as a reservoir for HIV-1 in the brain. With the emphasis on the development of an AIDS vaccine, understading the mechanims of HIV-1 infection in human brain is critical to the use of a vaccine. If reactivation of a latent infection from a sequestered site such as the brain can take place, immune reactivity as a result of vaccination would be necessary to clear the neuroinvasive virus as well as virus in the periphery.