The initial event in the life cycle of a virus is its interaction with receptors present on the surface of a cell. Understanding these interactions is important to our understanding of viral tropism, spread, and pathogenesis. The human polyomavirus, JCV, is the etiological agent of the fatal central nervous system (CMS) demyelinating disease, progressive multifocal leukoencephalopathy (PML). Following primary infection, JCV establishes a lifelong persistent infection in kidney and lymphoid tissues. In severely immunosuppressed individuals, the virus can spread to the CMS infecting both oligodendrocytes and astrocytes. The mechanisms that restrict JCV tropism for these cells and tissues and the mechanisms that allow for the spread of JCV from the periphery to the CNS are not understood. During the previous funding period we identified the cellular receptors for JCV, demonstrated that receptor recognition is a critical determinant of viral tropism, and shown that virus-receptor interactions initiate a series of signaling events that are critical for infection. A major goal of our current research is to define the consequences of the virus induced signal as it relates to viral tropism and growth. Our working hypothesis, which is based on our previous work and new preliminary data, is that JCV receptor interactions modulate the cellular environment to promote virus entry, replication, and spread within the host. We will address this hypothesis by asking the following questions: 1. How does virus binding to host cell receptors contribute to infection at the cellular level? 2. Is there a direct correlation between JCV receptor expression and virus tropism? 3. Is receptor expression altered in HIV infected patients with or without PML? and 4. How does JCV target its genome to the nucleus? The data resulting from these studies will yield novel insights into the pathogenesis of JCV induced disease and may lead to novel therapies to prevent or treat these diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Dimitriadi, Maria; Derdowski, Aaron; Kalloo, Geetika et al. (2016) Decreased function of survival motor neuron protein impairs endocytic pathways. Proc Natl Acad Sci U S A 113:E4377-86
Assetta, Benedetta; De Cecco, Marco; O'Hara, Bethany et al. (2016) JC Polyomavirus Infection of Primary Human Renal Epithelial Cells Is Controlled by a Type I IFN-Induced Response. MBio 7:
Haley, Sheila A; O'Hara, Bethany A; Nelson, Christian D S et al. (2015) Human polyomavirus receptor distribution in brain parenchyma contrasts with receptor distribution in kidney and choroid plexus. Am J Pathol 185:2246-58
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
Nelson, Christian D S; Ströh, Luisa J; Gee, Gretchen V et al. (2015) Modulation of a pore in the capsid of JC polyomavirus reduces infectivity and prevents exposure of the minor capsid proteins. J Virol 89:3910-21
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
Haley, Sheila A; Atwood, Walter J (2014) An animal model for progressive multifocal leukoencephalopathy. J Clin Invest 124:5103-6
Assetta, Benedetta; Maginnis, Melissa S; Gracia Ahufinger, Irene et al. (2013) 5-HT2 receptors facilitate JC polyomavirus entry. J Virol 87:13490-8

Showing the most recent 10 out of 41 publications