The overall goal of this project is to elucidate the mechanisms by which activation of JC virus in glial cells of the brain is influenced by HIV-1 infection. JC virus (JCV) is the etiologic agent of the neurodegenerative disease, progressive multifocal leukoencephalopathy (PML). JCV is normally latent in non-immunocompromised people, but it is activated in brains of individuals with AIDS. Because of the high incidence of PML in AIDS, we have hypothesized that HIV-1 plays a role greater than that expected of immunosuppression alone. We shall capitalize upon our extensive results of the last few years, which can be grouped in two categories. In one we have demonstrated the role of the Tat protein of HIV-1 in stimulating JCV late gene transcription and JCV DMA replication. In the other we have demonstrated that HIV-1 infection alters pathways of production and signal transduction of immunomodulators, including TGF-01, in the CNS. We propose to determine how the Smad nuclear effectors of TGF-31 interact with Tat and its cellular partner proteins Pura and Cyclin T1/ Cdk9 at JCV and PCNA promoter sequences. Our new double chromatin immunoprecipitation method will be employed in conjunction with functional studies on JCV DMA replication and gene transcription. We shall employ a microarray to identify genes in glial cells regulated by exposure to cytokines produced by HIV-1-infected cells. We shall employ a transgenic mouse model to test the hypothesis that factors produced by HIV-1-infected cells can influence JCV promoters in the CNS and play a role in early steps of PML development. Tissue from the Manhattan HIV Brain Bank will be used to determine whether TGF-P1 or its nuclear effectors, Smad3, Smad4 or Fasti, are localized or activated in specific cells of PML lesions. Results will help elucidate pathways of activation of JCV in the brain and will help target particular molecular interactions for therapy.
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