Vivek Nerurkar CNS Project
Genetic Determinants of JC Virus Replication and Pathogenicity
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 immunocompromised as a consequence of malignancies, granulomatous 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. With the advent of highly active antiretroviral therapy, HIV-infected patients are living longer but succumbing to infections and diseases including PML which are unrelated to their primary infection. Additionally, increases in the number of organ transplants in the United States and Europe with associated transient but severe immunosuppression, and chemotherapy and radiation therapy associated immunosuppression, significantly increase the chances of PML.PML is caused by JC virus (JCV), a member of the genus Polyomavirus in the family Papovaviridae. JCV, the opportunistic pathogen which triggers PML among immunocompromised individuals, is found among approximately 80% of the worlds population and infection is a common occurrence in childhood. Surprisingly, the route of transmission has not been established, due in part to the asymptomatic nature of the primary infection, but transmission via urine through an oral/respiratory route has been proposed. The primary site of infection is still uncertain, although a recent report proposes tonsils as such a site. It is likely that lymphocytes transport the virus from the primary site of infection to establish focal areas of infection. The proposed project will utilize in vitro systems to meticulously delineate steps involved in primary JCV infection and will investigate the genotypic basis for JCV infection. To better understand JCV pathogenesis, this proposal plans to focus on the areas which have been overlooked or have been controversial, such as the roles JCV coding and noncoding regions sequences play in pathogenicity and oncogenicity, and the probabilities that archetype JCV can replicate in human tonsil tissue. Answers to some of the proposed theses would lead to a better understanding of the disease, to the development of diagnostic tests to facilitate clinical observations, and to the opening of roads to effective treatments and preventive vaccines.
Supported by the Collaborative Neurological Sciences Award (S11 NS41833) to Vivek R. Nerurkar, Ph.D. from the National Institute of Neurological Disorders and Stroke, NIH