The objective of this project is to elucidate mechanisms of attachment of human JCV. Attachment mechanisms of related polyomaviruses are known in atomic detail, and involve interactions between the viral capsid protein VPl and cell surface receptors that are ganghosides. Little is known about the molecular basis of JCV attachment. We have overexpressed the VPl capsid protein of JCV and obtained small crystals. An integrated research program is proposed to (i) determine high-resolution structures of the JCV capsid protein VPl in complex with oHgosaccharide receptors (ii) determine structures of the JCV capsid protein VPl in complex with relevant portions of the serotonin receptor 5HT2aR, and (iii) determine high-resolution structures of the JCV capsid protein VPl in complex with inhibitors.
These aims should advance our understanding of JCV attachment to cells and point out strategies to intervene with the receptor interactions. As very few structure-function studies of virus-receptor interactions have been performed, the broader impact of this work will be in revealing general mechanisms by which pathogenic viruses recognize cellular receptors and cause organ-specific disease. We envision a high level of synergy between this project and projects 2 and 3, for the following reasons. The studies proposed here will provide a solid structural basis for understanding the binding modes of receptors and inhibitors to JCV, and this knowledge can then be directly used by the other projects to establish functional assays and to facilitate the development of effective small-molecule inhibitors. Vice versa, discoveries made by the other groups such as the identification of alpha-defensin as a JCV inhibtor can be directly used by us to provide a structural explanation for this interaction, which in turn can be used as platform for the development for other, strongly inhibitory ligands.

Public Health Relevance

To date, there are no adequate anti-viral treatments to resolve the/detrimental, and in some cases fatal, JCV-induced illness in affected individuals. The research proposed in project 1 will contribute to the development of general principles of virus-receptor interactions and reveal basic mechanisms of polyomavirus pathogenesis. Elucidation of these unifying themes may lead to identification of new targets for broadiv effective antiviral therapeutics

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS065719-05
Application #
8512815
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$174,374
Indirect Cost
Name
Brown University
Department
Type
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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

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