Progressive Multifocal Leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system (CNS) affecting patients with immunosuppressive disorders, especially those infected with the human immunodeficiency virus type 1 (HIV-1). The human neurotropic polyomavirus, JCV is the established etiologic agent of this disease which has the ability to productively infect and destroy oligodendrocytes, a subclass of glial cells that is responsible for production of myelin proteins and myelin sheaths in brain. The unique ability of JCV to replicate in oligodendrocytes rests on the activation of viral early gene transcription by a series of regulatory proteins present in glial cells. The product of the viral early gene, T-antigen, along with glial regulatory proteins, ensure subsequent events during the lytic cycle which include transcription of the viral late genes and replication to ensure subsequent events during the lytic cycle which include transcription of the viral late genes and replication of viral DNA. In addition to demyelination of white matter, histologic analysis of PML brain has revealed several morphological abnormalities including the appearance of enlarged oligodendrocytes with loss of normal chromatin, the presence of giant, bizarre astroyctes with pleiomorphic nuclei and mitotic figures in areas with no evidence for active viral replication. These observations suggest that expression of the viral early protein, T-evidence for active viral replication. These observations suggest that expression of the viral early protein, T-antigen, in the absence of lytic infection, may interfere with hot regulatory mechanisms, such as cell cycle circuitry pathways, to induce morphological alterations which are seen in pathological specimens of PML brain. In support of this concept, results from transgenic mice have indicated that expression of the JCV early protein, T-antigen, by a transgene containing the sequence for only the viral early genes induces dysmyelination of the CNS and several histological abnormalities similar to those seen in PML brain. According to our earlier results, the association of JCV T-antigen with myelin gene regulatory proteins and functional inactivation of these proteins may be responsible for the reduced levels of myelin gene expression in the brains of experimental animals. As such, in this research project we propose to: 1) investigate the molecular pathway whereby the JCV early protein, T-antigen, in the absence of viral lytic infection, may affect oligodendrocyte and astrocyte cell function; and 2) determine the molecular mechanism by which the JCV early protein, T-antigen, through its association with regulatory proteins orchestrates viral gene expression and replication during lytic infection of glial cells. Such comprehensive studies of viral host interaction at the molecular level should enable us to understand the molecular pathogenesis of viral-induced CNS disorders and provide us with critical information and biological regents for therapeutic intervention.
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