(Taken from application): Progressive multifocal leukoencephalopathy (PML), a fatal, demyelinating disease of the central nervous system (CNS), was first described in 1958 in patients with chronic lymphocytic leukemia and lymphoma. Prior to the AIDS era, PML was a very rare disorder occurring principally in patients immuno-compromised as a consequence of malignancies, granlulomatous disorders, collagen vascular disease or organ transplantation. Currently, AIDS is the most frequent condition associated with PML, with approximately 5% of AIDS patients developing PML. PML is caused by JC virus (JCV), a member of the genus Polyomavirus in the Papovaviridae. JCV infection occurs usually in early childhood, and 20 to 70% of infected individuals excrete JCV in their urine. Although the presumed route of infection is via the oral or respiratory tract, the primary site of replication is uncertain. A recent report proposes tonsils as such a site. It is likely that lymphocytes disseminate the virus from the primary site to establish focal areas of latent and persistent infection, as in the brain and kidney, respectively. Recent studies indicate that in PML patients, JCV is present in multiple tissues, while pathology is confined to the CNS. It has been suggested that reactivation occurs in the kidney during a prolonged impairment of T cell-mediated immune surveillance and/or by the production of cellular factors (e.g. cytokines) which influence viral expression. It is also possible that reactivation occurs in the brain, since it has been reported that JCV is present in the brains of some healthy individuals. Reactivation might then be the result of a direct or indirect interaction with an immunocompromising agent at this location. In vivo data suggest that genetic variations in the JCV transcriptional control region (TCR) or in coding sequences, in concert, with immunosuppression, contribute to the pathogenesis of PML. This proposal plans to 1) identify differences in replication capacity and transformation potential of JCV genotypic variants and derived chimeras; 2) investigate the basis for the restricted growth of archetype JCV evolves to yield multiple rearranged forms with altered pathogenic and oncogenic potential and define determinants of such evolution.
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