This program project brings together an interdisciplinary team of three scientists with unique expertise to functionally target and inhibit human polyomavirus infections. The polyomaviruses in general, and the human polyomaviruses in particular, have been shown to utilize distinct host cell carbohydrates and proteins to infect target cells and tissues. The human polyomavirus JCV is the causative agent of a fatal central nervous system demyelinating disease known as progressive multifocal leukoencephalopathy (PML). The majority of PML cases occur in patients with AIDS but recently PML has also been shown to occur in multiple sclerosis patients being treated with potent immunomodulatory drugs that inhibit immunosurveillance of the CNS. There are currently no drugs in the pipeline that target the virus directly and a major goal of this program is to identify compounds capable of directly inhibiting virus infection. This goal will be accomplished by close collaborative interactions between a team consisting of a polyomavirologist, a structural biologist, and a molecular geneticist/virologist. Project # 1 led by Professor Thilo Stehle will focus on structuraly characterizing and identifying sites on the virus that are critical for interacting with host cell surfaces. Project # 2 led by Professor Walter Atwood will introduce site-specific mutations in the virus based on these structures and functionally characterize the mutants. Project #2 will also further develop a drug lead identified in years 1-4 of this program project. Project # 3 led by Dr. Dan DiMaio will conduct genetic screens for factors that are critical for JCV invasion of host cells. The projects will be supported by a virus and pseudovirus production core at Brown University headed by Dr. Gretchen Gee. An administrative core will be housed at Brown University. The overall goal of this program is to use structural information and high throughput genetic screens to identify factors and targets that can be exploited to inhibit polyomavirus infection. The three major investigators on the team have built a strong working collaboration that is evidenced by the solid preliminary data and numerous joint publications that support this application.

Public Health Relevance

JCPyV causes a rare but devastating neurological disease in patients whose immune functions are compromised. Our work is focused on understanding how this common virus invades cells in the CNS to cause disease. We are also focused on identifying stages in the virus life cycle that can be targeted therapeutically to treat or prevent JCPyV induced disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS065719-09
Application #
9270607
Study Section
Neurological Sciences and Disorders C (NSD-C)
Program Officer
Wong, May
Project Start
2009-04-01
Project End
2019-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
9
Fiscal Year
2017
Total Cost
$1,302,650
Indirect Cost
$268,750
Name
Brown University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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:
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
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
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
Ströh, Luisa J; Maginnis, Melissa S; Blaum, Bärbel S et al. (2015) The Greater Affinity of JC Polyomavirus Capsid for ?2,6-Linked Lactoseries Tetrasaccharide c than for Other Sialylated Glycans Is a Major Determinant of Infectivity. J Virol 89:6364-75
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
Yatawara, Achani; Gaidos, Gabriel; Rupasinghe, Chamila N et al. (2015) Small-molecule inhibitors of JC polyomavirus infection. J Pept Sci 21:236-42
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

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