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

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Brown University
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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
Neu, Ursula; Allen, Stacy-Ann A; Blaum, Barbel S et al. (2013) A structure-guided mutation in the major capsid protein retargets BK polyomavirus. PLoS Pathog 9:e1003688
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
Maginnis, Melissa S; Stroh, Luisa J; Gee, Gretchen V et al. (2013) Progressive multifocal leukoencephalopathy-associated mutations in the JC polyomavirus capsid disrupt lactoseries tetrasaccharide c binding. MBio 4:e00247-13
Lipovsky, Alex; Popa, Andreea; Pimienta, Genaro et al. (2013) Genome-wide siRNA screen identifies the retromer as a cellular entry factor for human papillomavirus. Proc Natl Acad Sci U S A 110:7452-7
Yatawara, Achani K; Hodoscek, Milan; Mierke, Dale F (2013) Ligand binding site identification by higher dimension molecular dynamics. J Chem Inf Model 53:674-80

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