- PROJECT 2 The initial interaction of JCPyV with its host involves recognition of specific receptor complexes on cells. Recognition of these receptors leads to virus penetration of the host cell membrane, trafficking of the virion to the endoplasmic reticulum, and the eventual delivery of the dsDNA genome to the cell nucleus. Our team, supported by this program project, elucidated the critical components of the JCPyV receptor complex and determined that the major capsid protein VP1 was responsible for directing the virus to the ER. We developed novel tools to study not only lab adapted strains of JCPyV but also mutant forms of the virus that have been reported to arise in the brains of patients with PML. These mutant forms of JCPyV have lost the ability to recognize the sialic acid receptor and as a consequence are no longer infectious in most cell types examined. We hypothesize that these mutants either recognize alternative receptors which are yet to be identified or that they have gained the capacity to spread directly from cell to cell bypassing the requirement for cell surface receptors. Our approach in project 2 is to use pseudoviruses developed in core B to further explore potential receptor usage by these mutants. We will also explore the possibility that these mutants, are capable of direct cell to cell spread by engineering the mutations into an infectious JCPyV clone and following their growth after transfection of the genomes into different cell types grown as confluent monolayers. Regardless of the mechanism of infection (receptor mediated OR direct cell to cell spread) these viruses must all traffic to the ER to begin the uncoating process for eventual delivery of their genomes to the nucleus. In the last funding cycle we discovered that the dihydroquinozolinone compound Retro-2cycl potently prevents JCPyV trafficking to the ER and substantially reduces initial infection and infectious spread. Our goal now is to define its mechanism of action, to identify its cellular targets, and to optimize the existing compound so that a therapeutic window of inhibition can be determined.

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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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