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.

Public Health Relevance

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.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brown University
Schools of Medicine
United States
Zip Code
Maginnis, Melissa S; Nelson, Christian D S; Atwood, Walter J (2015) JC polyomavirus attachment, entry, and trafficking: unlocking the keys to a fatal infection. J Neurovirol 21:601-13
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
O'Hara, Bethany A; Rupasinghe, Chamila; Yatawara, Achani et al. (2014) Gallic acid-based small-molecule inhibitors of JC and BK polyomaviral infection. Virus Res 189:280-5
Carney, Daniel W; Nelson, Christian D S; Ferris, Bennett D et al. (2014) Structural optimization of a retrograde trafficking inhibitor that protects cells from infections by human polyoma- and papillomaviruses. Bioorg Med Chem 22:4836-47
Nelson, Christian D S; Carney, Dan W; Derdowski, Aaron et al. (2013) A retrograde trafficking inhibitor of ricin and Shiga-like toxins inhibits infection of cells by human and monkey polyomaviruses. MBio 4:e00729-13
Gee, Gretchen V; O'Hara, Bethany A; Derdowski, Aaron et al. (2013) Pseudovirus mimics cell entry and trafficking of the human polyomavirus JCPyV. Virus Res 178:281-6
Nelson, Christian D S; Derdowski, Aaron; Maginnis, Melissa S et al. (2012) The VP1 subunit of JC polyomavirus recapitulates early events in viral trafficking and is a novel tool to study polyomavirus entry. Virology 428:30-40
Shen, Peter S; Enderlein, Dirk; Nelson, Christian D S et al. (2011) The structure of avian polyomavirus reveals variably sized capsids, non-conserved inter-capsomere interactions, and a possible location of the minor capsid protein VP4. Virology 411:142-52
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

Showing the most recent 10 out of 34 publications