PROJECT 1 JCPyV infection causes a fatal central nervous system disease, progressive multifocal leukoencephalopathy, PML, for which there are no effective treatments. A thorough understanding of the structure-function relationships of this human pathogen is key for the development of effective therapies against PML in the future. We propose to use structure-function approaches to identify molecules that can bind to the recombinantly produced JCPyV capsid protein VP1 with high affinity (Specific Aim 1). Since the initial hits likely will not be very specific, we will optimize them by conducting binding assays with structurally related compounds using NMR spectroscopy, and verify binding by crystallography as well as in biological assays in collaboration with the Atwood and DiMaio groups (projects #2 and #3). We will furthermore structurally characterize receptor-switching mutants of JCPyV VP1 pentamers and their ligand-binding properties (Specific Aim 2). Our preliminary results show that JCPyV can engage a range of sialylated glycans, but not all of these interactions lead to an infection. We will engineer JCPyV VP1 mutants that selectively use only a single glycan receptor, and we will crystallize the VP1 proteins in complex with the receptor to define specificities and also analyze the corresponding pseudoviruses in collaboration with project #2 and core B for cell binding and entry. Dr. DiMaio (project #3) will determine if viruses targeted to different receptors display different trafficking patterns. In a second part of this aim, we will characterize ligand-binding properties and specificities of JCPyV isolates from PML patients using glycan microarray screening as well as crystallography. Finally, we will perform structure-function analyses of entire JCPyV pseudoviruses (Specific Aim 3). Binding sites for some receptors may lie between VP1 pentamers on the virion surface, and such sites will not be present in the context of the recombinantly expressed pentamers alone. JCPyV pseudoviruses have recently been generated by the Atwood group (project #2), and they faithfully replicate essential functions of the virus in attachment and entry. The JCPyV pseudovirus particles will be analyzed structurally with respect to their ligand binding properties as well as in glycan microarrays.

National Institute of Health (NIH)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brown University
United States
Zip Code
Luo, Yong; Motamedi, Nasim; Magaldi, Thomas G et al. (2016) Interaction between Simian Virus 40 Major Capsid Protein VP1 and Cell Surface Ganglioside GM1 Triggers Vacuole Formation. MBio 7:e00297
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
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
Jelcic, Ivan; Combaluzier, Benoit; Jelcic, Ilijas et al. (2015) Broadly neutralizing human monoclonal JC polyomavirus VP1-specific antibodies as candidate therapeutics for progressive multifocal leukoencephalopathy. Sci Transl Med 7:306ra150
Yatawara, Achani; Gaidos, Gabriel; Rupasinghe, Chamila N et al. (2015) Small-molecule inhibitors of JC polyomavirus infection. J Pept Sci 21:236-42
Ströh, Luisa J; Maginnis, Melissa S; Blaum, Bärbel S et al. (2015) The Greater Affinity of JC Polyomavirus Capsid for α2,6-Linked Lactoseries Tetrasaccharide c than for Other Sialylated Glycans Is a Major Determinant of Infectivity. J Virol 89:6364-75
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
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
Haley, Sheila A; Atwood, Walter J (2014) An animal model for progressive multifocal leukoencephalopathy. J Clin Invest 124:5103-6
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

Showing the most recent 10 out of 24 publications