The control region of the HIV-1 genome is composed of multiple distinct regulatory elements, each exerting their effect on viral gene transcription by interacting with various cellular proteins. Some of the participant proteins are inducible and their expressiodactivity in cells is regulated by external stimuli such as cytokines and immunomodulators. These cytokines, such as TNFalpha and TGFbeta, whose levels are increased in patients with AIDS can trigger distinct signaling pathways that modulate expression of the HIV-1 genome during the course of infection. Examination of the TGFbeta signaling pathway in human CNS cell lines has revealed that downstream regulators of this network, i.e. Smad-3 and Smad-4, can modulate transcription of the viral genome at the immediate early stage after infection, when HIV-1 Tat is the key viral protein that is produced. Evidently, Smad-3 and Smad-4, by associating with the CEBP transcription factor, a potent stimulator of HIV-1, modulates the level of viral gene expression in human astrocytes. At the early and late phases of viral infection, when the viral regulatory proteins Tat and Vpr are produced, respectively, other signaling pathways such as Wnt, which is important for neural cell development and function, may play a central role by controlling the Tat stimulatory activity of viral gene transcription. This event is mediated through the interaction of Wnt regulatory proteins, TCF-4 and beta-catenin with Tat and its cellular partner, cyclin T. These observations provide a strong basis to hypothesize that the physical and functional communication between the signaling pathways which are operative in CNS cells, along with the HIV-1 genome and its regulatory proteins, can dictate the level of viral gene expression and replication during the course of disease in the brain. In this research project we will utilize molecular biological, virological, and biochemical approaches to decipher the mechanism(s) whereby signaling pathways and their downstream regulators affect the state of viral gene expression at the immediate early, early, and late phases of CNS infection. The outcome of these studies will provide important information which can be utilized in devising molecular strategies toward inhibition of viral gene expression by inducing host factors.
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