Research Project
2655487
In addition to immune dysfunction, AIDS is characterized by frequent central nervous system (CNS) abnormalities, including severe encephalopathy, and peripheral neuropathy. Broad clinical and biological manifestations such as fever, ataxia, astrogliosis, microglial proliferation, etc. involving cells not infected with virus strongly suggest that such effects may be mediated indirectly by cytokines produced in the CNS. It is believed that in addition to infecting macroglial/microglial and astroglial cells, the virus may affect uninfected or latently infected neighboring brain cells. It is suggested that the HIV-1 encoded regulatory protein, Tat, may facilitate the trans-cellular communication process through which Tat released from the viral-infected cells can be taken up by uninfected cells and influence the expression of several important cellular genes, including cytokines. Our preliminary results indicate that the HIV-1 Tat protein stimulates expression of TGFbeta-1, a potent cytokine with well defined immunosuppressive activity, in human astrocyte glial cells. We hypothesize that Tat transactivation of the TGFbeta-1 promoter rests in the induction/activation of functional regulatory factor(s) in glial cells which enhance TGFbeta-1 gene expression by interacting with cis-acting elements within the regulatory region. Our proposed experiments are designed to employ molecular biology and genetic approaches to identify the regulatory components (cis-and trans-) that are responsible for activation of TGFbeta-1 in glial cells. The information gained from these analyses should increase our current understanding of cell-type specific gene transcription in the central nervous system (CNS) and facilitate future approaches to deciphering regulation of cytokine gene expression in the CNS.
