Progressive Multifocal Leukoencephalopathy (PML) is a major life threatening complication in patients with underlying immunosuppressive disorders (e.g. AIDS) and in patients undergoing immunotherapy for autoimmune diseases such as multiple sclerosis, Crohn's disease, severe plaque psoriasis, systemic lupus erythematosis, hematologic malignancies, and rheumatoid arthritis. The disease is paradoxically caused by a common human polyomavirus following activation from a latent to a lytic phase of growth. There are several critical gaps in our understanding of the basic biology of PML. First, the anatomical site of virus latency is not known but kidney, tonsil, bone marrow, and brain have all been postulated to be involved. Second, the mechanisms that govern latency versus lytic growth of the virus are not well understood. Third, the mechanisms of viral spread to the CNS and within the CNS are not known. We hypothesize that virus induced signals reprogram the cellular environment to promote replication and spread and that epigenetics plays a role in governing the balance between latency and activation. The experiments proposed here will define these signals and the molecular pathways involved in viral pathogenesis. These mechanisms and pathways may be amenable to pharmacological intervention.
This proposal focuses on understanding how the JC polyomavirus (JCV) alters its environment to promote its growth and spread in multiple human tissues. JCV infects greater than 70% of the human population worldwide and causes a fatal central nervous system disease in humans known as Progressive Multifocal Leukoencephalopathy or PML in individuals with compromised immune systems. Our work should lead to the development of therapeutic approaches to prevent or treat JCV induced disease in humans.
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|Zins, Stephen R; Nelson, Christian D S; Maginnis, Melissa S et al. (2014) The human alpha defensin HD5 neutralizes JC polyomavirus infection by reducing endoplasmic reticulum traffic and stabilizing the viral capsid. J Virol 88:948-60|
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|Maginnis, Melissa S; Haley, Sheila A; Gee, Gretchen V et al. (2010) Role of N-linked glycosylation of the 5-HT2A receptor in JC virus infection. J Virol 84:9677-84|
|Neu, Ursula; Stehle, Thilo; Atwood, Walter J (2009) The Polyomaviridae: Contributions of virus structure to our understanding of virus receptors and infectious entry. Virology 384:389-99|
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