The human polyomavirus, JCV, establishes a lifelong persistent infection and is generally not associated with disease in healthy individuals. In immunosuppressed patients reactivation and spread of JCV to the central nervous system causes a fatal demyelinating disease known as progressive multifocal leukoencephalopathy (PML). Our immediate goals are to define the structural features of the JCV surface that allow for cell binding and infection and to identify molecules that antagonize these interactions. In this project we will use structural information provided by project #1 to guide mutagenesis and testing of amino acid residues in the virus capsid that are hypothesized to interact directly with cell surfaces allowing for productive infection. We will work closely with project #3 to identify and screen compounds for their ability to antagonize these interactions. In preliminary experiments we've established that two small molecular weight human alpha defensins potently inhibit infection by JCV, BKV, and SV40 most likely by binding to a shared domain on the virion surface.
Specific aim #3 of this project will focus on determining the mechanism of action of alpha defensin inhibition of JCV infection. Working together with the Pis of projects 1 and 3 we will determine the structural basis for inhibition by these molecules

Public Health Relevance

Reactivation of JCV in the setting of prolonged immunosuppression or immunomodulation leads to the devastating central nervous system demyelinating disease, progressive multifocal leukoencephalopathy (PML). AIDS patients are at the greatest risk for developing PML and the time from diagnosis to death is on the order of one to two years. Multiple sclerosis patients being treated with highly promising immunomodulatory druas are also at increased risk for the development of this life-threatenina opportunistic

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS065719-05
Application #
8512816
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
$386,955
Indirect Cost
$148,095
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
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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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