Acquired immunodeficiency syndrome (AIDS) is frequently associated with multiple disorders of the CNS. At least 60% of AIDS patients develop symptoms of neurologic disease and 90% demonstrate neuropathologic abnormalities at autopsy. The common neurologic problems include primary lymphoma, subacute encephalitis, white matter degeneration and demyelination. Detection of HIV-1 DNA in the brain and recovery of infectious virus from cerebrospinal fluid of AIDS patients strongly suggest that HIV is responsible for some of the neurologic complications found in these individuals. HIV-1 has been shown to infect glial cells in vitro and has been detected in oligodendrocytes and astroglial cells in vivo. The association of CNS dysfunction with the presence of infectious virus in AIDS patients prompted us to investigate the regulation of HIV-1 expression in glial cells. Our preliminary results indicate that a novel regulatory circuit, distinct from those in lymphoid cells, mediates expression from the viral long terminal repeat (LTR). Deletion analysis within the HIV-LTR has revealed the Tat activation responsive element (TAR) spanning the leader sequence of the viral transcripts. The presence of TAR appears to be an absolute requirement for a functional Tat in every cell type examined thus far. However, we have recently demonstrated in a glial cell line that Tat can significantly stimulate expression of the LTR in a TAR-independent manner. fine deletion mapping and hybrid promoter constructs have demonstrated that the newly identified Tat-responsive element corresponds to a sequence within the viral promoter previously identified as the HIV- 1 enhancer of kB domain. We hypothesize that the TAR-independent transactivation of the LTR promoter rests in the induction/activation of a functional positive regulatory trans-acting factor(s) unique to glial cells by Tat which enhances viral RNA synthesis by interacting with kB cis-acting transcriptional elements. Our proposed experiments are designed to: (1) identify critical nucleotides within the HIV-1 enhancer that are responsive to the tat protein in the LTR promoter; (2) use a Tat-producing glial cell line in order to define the components of the transcription apparatus that interact with this element and/or Tat to stimulate transcription of the HIV-1-LTR promoter. The information gained from these manipulations and analyses should increase our understanding about molecular mechanisms involved in viral replication and pathogenesis in CNS cells.
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